Nucleotide Analogs

ABSTRACT

Disclosed herein, inter alia, are acyclic nucleotide analogs and methods of using an acyclic nucleotide analog for treating and/or ameliorating a papillomavirus infection.

This application is a continuation of U.S. application Ser. No.16/535,284, filed Aug. 8, 2019, which is a continuation of U.S.application Ser. No. 15/758,328, filed Mar. 7, 2018, issued as U.S. Pat.No. 10,377,782 on Aug. 13, 2019, which claims the benefit of U.S.Provisional Application No. 62/380,205 filed Sep. 15, 2015, which arehereby incorporated by reference in their entirety and for all purposes.

FIELD

The present application is directed to nucleotide analogs,pharmaceutical compositions that include a disclosed nucleotide analog,and processes for their synthesis. The invention also includes methodsof treating diseases and/or conditions with the disclosed nucleotideanalog, alone or in combination therapy with one or more other agents,including in particular for the treatment of a viral infection in a hostsuch as that caused by a papillomavirus.

BACKGROUND OF THE INVENTION

Viruses are infectious particles that can replicate their DNA or RNAonly within host cells. Viral infections may lead to mild to severeillnesses in humans and mammals, and in some instances, can result indeath. Examples of viral infections include hepatitis B and C, smallpox,herpes simplex, cytomegalovirus, human immunodeficiency virus (HIV),influenza, adenovirus, chickenpox, BK virus, JC virus andpapillomavirus. Viral infection can lead to cancer in humans and otherspecies. Viruses known to cause cancer include human papillomavirus(HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and EpsteinBarr virus (EBV).

Papillomaviruses are a group of non-enveloped DNA viruses, which inhumans infect keratinocytes of skin and mucous membranes including inthe anogenital area. They are known to cause skin warts, genital warts,and respiratory papillomatosis and cancer. In women, Papillomavirusescan cause precancerous cervical lesions which lead to cervicalintraepithelial neoplasia, vaginal and anal intraepithelial neoplasia,and ultimately cervical cancer.

Several species of the alpha-papillomavirus genus contain high risktypes of HPV which are more likely to lead to human cancer. Most of thecancer-causing HPV types are from the alpha-7 and alpha-9 species andinclude types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73,and 82. Cancers caused by HPV include cervical, rectal, penile, vaginaland oropharyngeal cancer. The most common cancer-causing HPV types are16 and 18. HPV-16 and -18 are reported to be the cause of 70% ofcervical cancers; and 90% of venereal warts are caused by the low riskHPV types 6 and 11. The presence of a HPV infection can be detectedusing a PAP smear and/or DNA probe testing with products such asCEREVISTA® (Hologic), COBAS® (Roche) and other commercially availableproducts. Currently available HPV DNA tests detect DNA from 14 high-riskHPV types, including HPV-16 and HPV 18. Vaccines have been developed forHPV 6, 11, 16 and 18, which may be effective if administered prior tosexual debut. However, the HPV vaccines may provide little benefit insexually active women who have already been infected with HPV.

HPV replication and viral DNA synthesis that produce mature virionsfirst takes place in the basilar layer of cervical epithelial cells andamplifies to involve the suprabasilar cells as the infection proceeds.After months or years of infection, elements of the HPV DNA episome canbecome integrated into the epithelial cell genomic DNA. The integratedelements generally include viral LI, the long control region (LCR), andthe E6 and E7 oncogenes. This results in overexpression of E6 and E7oncoproteins that over time cause the loss of cell cycle controls andprogression to cervical cancer. However, in cervical cancer cell lineswhich have integrated HPV DNA such as HeLa (HPV18), SiHa (HPV16), CaSki(HPV16) and Mel80 (HPV39) productive viral replication is not occurring.Thus, studies of compounds which inhibit cell division of human cervicalcancer cell lines that contain integrated E6 and E7 do not provideknowledge about the inhibition of productive viral DNA synthesis.Additional information regarding HPV and its replication is provided inFields Virology 1662-1703 (David M. Knipe, Ph.D. and Peter M. Howley, MDeds., 6th ed., Wolters Kluwer, 2013) (2001), which is herebyincorporated by reference in its entirety. There is presently noapproved antiviral treatment for a human papillomavirus infection.

One class of antiviral drugs are nucleoside or nucleotide analogs, whichinterfere with DNA or RNA replication necessary for viral growth.Examples of antiviral nucleoside analogs include RETROVIR®, ZOVIRAX®,CYTOVENE®, EPIVIR® and EMTRIVA®.

Nucleotide analogs include the acyclic nucleoside phosphonates (ANPs).Nucleotide analogs were initially designed to circumvent the firstphosphorylation of a parent nucleoside. This first phosphorylation hasbeen identified as the limiting step in the generation of the activenucleoside triphosphate. Examples of ANPs include adefovir, tenofovirand cidofovir (CDV) which are active against human infections such asHBV, HIV and CMV, respectively. ANPs are known in the art to be poorlyadsorbed from the gastrointestinal tract of mammals due to 1) theirmolecular weight and 2) the presence of a double negative charge on thephosphonate moiety. Because of their poor oral pharmacokineticproperties, ANPs have been converted to prodrugs to produce clinicallyuseful therapeutic agents. For example, tenofovir is marketed asVIREAD®; a disoproxil (diester) fumarate salt, for the treatment of HIV.Adefovir is marketed as HEPSERA®; a dipivoxil ester, for the treatmentof HBV.

Additional examples of ANP prodrugs include pradefovir (Phase III) andGS-7340. GS-7340, tenofovir alafenamide, has been approved for thetreatment of HIV and is part of the fixed-dose combinations GENVOYA®,ODEFSEY® and DESCOVY®. See, for example, Pradere, U. et al., “Synthesisof Nucleoside and Phosphonate Prodrugs”, Chemical Reviews, 2014, 114,9154-9218 and the structures below.

An alternate approach to increasing the oral bioavailability of ANPs hasbeen to prepare alkoxyalkyl monoesters or alkyl monoesters. See, forexample, Beadle et al., “Synthesis and Antiviral Evaluation ofAlkoxyalkyl Derivatives of9-(S)-(3-Hydroxy-2-phosphono-methoxypropyl)adenine againstCytomegalovirus”, J. Med. Chem., 2006, 49:2010-215; Painter et al.,“Evaluation ofHexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)Propyl]-Adenine, CMX157, asa Potential Treatment for Human Immunodeficiency Virus Type 1 andHepatitis B Virus Infections,” Antimicrobial Agents and Chemotherapy,2007, 51:3505-3509; Valiaeva et al., “Synthesis and antiviral evaluationof alkoxyalkyl esters of acyclic purine and pyrimidine nucleosidephosphonates against HIV-1 in vitro”, Antiviral Research, 2006,72:10-19; Aldern et al., “Update and Metabolism of Cidofovir andOleyloxyethyl-cidofovir in Human Papillomavirus Positive ME-180 HumanCervical Cancer Cells” Abstract 173 Antiviral Res., 2007, 74(3):A83;Hostetler et al., “Enhanced Anti-proliferative effects of alkoxyalkylesters of cidofovir in human cervical cancer cells in vitro” Mol. CancerTher., 2006, 51(1):156-158; Trahan et al., “Anti-proliferative Effectsof Octadecyloxyethyl-Phosphonomethoxyethylguanine (ODE-PMEG) on theGrowth of Human Papilloma Virus Positive Cervical Carcinoma (ME-180)Cells in Vitro and Solid Tumors in Athymic Nude Mice” Abstract 85Antiviral Res., 2009, 82(2):A42; Valiaeva et al., “Anti-proliferativeEffects of Octadecyloxyethyl 9-[2-(Phosphonomethoxy)Ethyl] Guanineagainst Me-180 Human Cervical Cancer Cells in vitro and in vivo”,Chemotherapy, 2010, 56:(1)54-59; Valiaeva et al., “Synthesis andantiviral evaluation of 9-(S)-[3-alkoxy-2-(phosphonomethoxy)-propyl]nucleoside alkoxyalkyl esters: Inhibitors of hepatitis C virus and HIV-1replication”, Bioorganic and Medicinal Chemistry, 2011, 19:4616-4625. Inaddition, see the patent applications and patents to Hostetler: U.S.Pat. Nos. 6,716,825; 7,034,014; 7,094,772; 7,098,197; 7,652,001;7,452,898; 7,790,703; 7,687,480; 7,749,983; 7,994,143; 8,101,745;8,008,308; 8,193,167; 8,309,565; 8,318,700; 8,846,643; 8,710,030;8,889,658, 9,156,867; 9,387,217 and US 2015/0080344; The Regents of TheUniversity of California: WO 1996/39831; WO 2001/039724; WO 2005/087788;WO 2006/066074; WO 2006/076015; and WO 2011/130557; and the Dana FarberCancer Institute, Inc.: WO/1998/38202.

A hexadecyloxypropyl ester of cidofovir, HDP-CDV (brincidofovir), iscurrently being developed for the treatment of adenovirus. The drug iscurrently in Phase III. See, for example, U.S. Pat. Nos. 9,006,218;8,993,542; 8,962,829; 8,614,200; 8,569,321; 7,994,143; 7,749,983;6,599,887; 6,448,392; WO 2007/130783; WO 2008/133966; WO 2009/094190; WO2011/011519; WO 2011/011710; WO 2011/017253 and WO 2011/053812.

The synthesis of phosphonomethoxyethyl or1,3-bis(phosphonomethoxy)propan-2-yl lipophilic esters of acyclicnucleoside phosphonates, and alkyl diesters of ANPs have been disclosedSee, Holy et al., “Structure-Antiviral Activity Relationship in theSeries of Pyrimidine and Purine N-[2-(2-Phosphono-methyloxy)ethyl]Nucleotide Analogues. Derivatives Substituted at the Carbon Atoms of thebase”, J. Med. Chem., 1999, 42(12):2064-2086; Holy et al., “Synthesis ofphosphonomethoxyethyl or 1,3-bis(phosphonomethoxy) propan-2-yllipophilic esters of acyclic nucleoside phosphonates”, Tetrahedron,2007, 63:11391-11398. The synthesis of anti-cancer phosphonate analogshas also been investigated; see, WO 2004/096235; WO 2005/066189 and WO2007/002808. The synthesis of prodrugs of ANPs has also beeninvestigated; see, WO 2006/114064 and WO 2006/114065. The synthesis ofpurine nucleoside monophosphate prodrugs for the treatment of cancer andviral infections has also been investigated; see, WO 2010/091386.

Certain acyclic nucleoside phosphonate diesters are disclosed in U.S.Pat. Nos. 8,835,630; 9,156,867; and 9,387,217.

While there are currently no approved pharmaceutical drugs that are usedto treat an early HPV infection that has not yet progressed to cancer,certain epicatechins, epicatechin oligomers or thiolated epicatechinsfrom Theobroma cacao for treatment of genital warts have been disclosed;see, US 2015/0011488.

The pyrimidine, 5-fluorouracil, is active against HPV but is highlytoxic. The broad spectrum antiviral agent GSK983 has been shown to haveanti HPV activity but has not been studied extensively in humans yet.Other small molecules having anti-HPV activity include the cobaltcomplex CDC-96, indol-3-carbinol (I3C) and the immunomodulatoryImiquimod, see, US 2015/0011488.

To date, there are no approved pharmaceutical drugs that are used totreat an early HPV infection that has not yet progressed to cancer.Provided herein are solutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

The present invention provides new compounds, composition and methodsthat for the treatment of viral diseases including in particularincluding those caused by papillomaviruses. Specifically, the inventionprovides compounds of Formula I:

wherein: B¹ is a naturally occurring purine, a naturally occurringpyrimidine, a non-naturally occurring purine or a non-naturallyoccurring pyrimidine. In one embodiment, B¹ is selected from adenine,hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine,2,6-diaminopurine, cytosine, thymine or uracil, guanine-7-yl,adenine-9-yl, cytosine-1-yl, thymin-1-yl, uracil-1-yl,2,6-diaminopurin-9-yl, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanineor 9-deazaguanine. In embodiments, B¹ is selected from:

Z¹ and Z² are independently O or NR^(Z). R^(Z) is hydrogen or anoptionally substituted C₁₋₄ alkyl. R¹ is an optionally substituted—C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄ alkynyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkyl(C₁-C₄ alkyl)-, anoptionally substituted cycloalkenyl, an optionally substitutedcycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-,

and R² is an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or R¹ and R² can be taken together to form a moiety selected from anoptionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system. R³ is hydrogen, optionallysubstituted alkyl or optionally substituted heteroalkyl; each R⁴ isindependently hydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A);each R^(4A) is independently hydrogen, an optionally substituted C₁₋₂₄alkyl or an optionally substituted aryl; each R⁵, each R⁶ and each R⁸are independently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰are independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₅ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;each a and each b are independently 1, 2, 3 or 4; and each c and each dare independently 0, 1, 2 or 3.

In an alternative embodiment, when B¹ is

R¹³ can be an unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆cycloalkyl and R³ can be selected from optionally substituted alkyl suchas CH₃, CH₂OH, CH₂F, CHF₂, CF₃, or optionally substituted heteroalkylsuch as OCH₃.

PMEG diphosphate is one of the most potent chain-terminating inhibitorsof DNA polymerases alpha, delta and epsilon (Kramata P, Votruba I, OtováB, Holý A. Different inhibitory potencies of acyclicphosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha,delta and epsilon. Mol Pharmacol. 1996 June; 49(6):1005-11. PubMed PMID:8649338). However its inhibition of polymerases beta, gamma and epsilonis less pronounced. Pol delta and epsilon are involved in DNA repair andhave exonuclease activity. Kramata et al have shown that PMEG-terminatedprimers cannot be repaired by pol delta (Kramata P, Downey K M, PaborskyL R. Incorporation and excision of 9-(2-phosphonylmethoxyethyl)guanine(PMEG) by DNA polymerase delta and epsilon in vitro. J Biol. Chem. 1998Aug. 21; 273(34):21966-71. PubMed PMID: 9705337).

The mechanism of action of the antiviral compounds of the presentinvention that are metabolized to PMEG diphosphate is not known withcertainty, however, it is possible that rapidly dividing epithelialcells cannot effectively repair PMEG terminated viral primers. Certainof the active compounds described herein release PMEG very slowly whichtends to moderate intracellular levels of PMEG diphosphate, the activemetabolite favoring antiviral activity and inhibition of HPV DNAsynthesis, while higher intracellular levels of PMEG diphosphate(resulting from prodrugs that release PMEG diphosphate more quickly inthe cell) lead to inhibition of cell division in a number of humancancers. This invention is based on the discovery that theanti-proliferative activity of the active metabolite PMEG diphosphatecan be separated from the antiviral action of the active metabolite PMEGdiphosphate by careful selection of the prodrug moiety to moderate therelease rate of the active metabolite in the cell.

In embodiments, the invention describes compounds with antiviralactivity against a papillomavirus in the absence of a significantanti-proliferative host cell effect.

The invention includes antiviral agents that selectively inhibit and/orblock viral DNA synthesis and/or the production of virions of high riskHPV types. Inhibition and/or blockage of viral DNA synthesis and/or theproduction of virions of high risk HPV types can then eradicate thepapillomavirus infection before cellular changes take place which canlead to invasive cancers, such as those described herein, and thusrepresent an advance in the art.

One embodiment of the invention provides an effective amount of anantiviral compound of Formula (I), or a pharmaceutically acceptable saltthereof, for treating a host infected with a human papillomavirus, byinhibiting the synthesis of viral DNA. Another embodiment disclosedherein is a method for treating a host infected with a humanpapillomavirus that includes contacting a cell infected with the humanpapillomavirus and/or administering to a subject infected with the humanpapillomavirus an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the humanpapillomavirus can be treated by selectively inhibiting viralreplication by inhibiting the synthesis of viral DNA.

The present invention includes at least the following features:

(a) an antiviral compound of Formula I as described herein, andpharmaceutically acceptable salts and prodrugs thereof (each of whichand all subgenera and species thereof considered individually andspecifically described);

(b) an antiviral Formula I as described herein, and pharmaceuticallyacceptable salts and prodrugs thereof, for use in treating or preventinga viral infection such as papillomavirus in a host;

(c) use of Formula I, and pharmaceutically acceptable salts and prodrugsthereof in the manufacture of a medicament for use in treating orpreventing a viral disease such as papillomavirus in a host;

(d) a process for manufacturing a medicament intended for thetherapeutic use for treating or preventing treating or preventing aviral disease such as papillomavirus in a host further hereincharacterized in that Formula I as described herein is used in themanufacture;

(e) a pharmaceutical formulation comprising an effective host-treatingamount of the Formula I or a pharmaceutically acceptable salt or prodrugthereof together with a pharmaceutically acceptable carrier or diluent;

(f) Formula I as described herein in substantially pure form, includingsubstantially isolated from other chemical entities (e.g., at least 90or 95%);

(g) processes for the manufacture of the compounds of Formula I andsalts, compositions, dosage forms thereof; and

(h) processes for the preparation of therapeutic products that containan effective amount of Formula I, as described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ represent substituentsthat can be attached to the indicated atom. An R group may besubstituted or unsubstituted. If two “R” groups are described as being“taken together” the R groups and the atoms they are attached to canform a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. Forexample, without limitation, if R^(a) and R^(b) of an NR^(a)R^(b) groupare indicated to be “taken together,” it means that they are covalentlybonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more of the indicated substituents. If nosubstituents are indicated, it is meant that the indicated “optionallysubstituted” or “substituted” group may be substituted with one or moregroup(s) individually and independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, an amino, a mono-substituted amino group anda di-substituted amino group.

As used herein, “C_(a) to C_(b),” “C_(a)-C_(b),” “C_(a-b)” and the likein which “a” and “b” are integers, refer to the number of carbon atomsin an alkyl, alkenyl or alkynyl group, or the number of carbon atoms inthe ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclylgroup. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl,ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl orring of the heterocyclyl can contain from “a” to “b”, inclusive, carbonatoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkylgroups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—,(CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b”are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest rangedescribed in these definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group may be unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur. The number of atoms in the ring(s) of a heteroaryl group canvary. For example, the heteroaryl group can contain 4 to 14 atoms in thering(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).Furthermore, the term “heteroaryl” includes fused ring systems where tworings, such as at least one aryl ring and at least one heteroaryl ring,or at least two heteroaryl rings, share at least one chemical bond.Examples of heteroaryl rings include, but are not limited to, furan,furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole,benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine,pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnolineand triazine. A heteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refer to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfurand nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl maybe quaternized. Heterocyclyl or heteroalicyclic groups may beunsubstituted or substituted. Examples of such “heterocyclyl” or“heteroalicyclyl” groups include but are not limited to, 1,3-dioxin,1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane,1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole,1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, trioxane,hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline,isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine,piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone,pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran,tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide,thiamorpholine sulfone and their benzo-fused analogs (e.g.,benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aryl(alkyl) may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaryl(alkyl) maybe substituted or unsubstituted. Examples include but are not limited to2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl),pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl),and their benzo-fused analogs.

A “(heteroalicyclyl)alkyl” and “(heterocyclyl)alkyl” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of a(heteroalicyclyl)alkyl may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—) and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or(heterocyclyl)alkyl is defined herein. A non-limiting list of alkoxysare methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, benzyloxy, hexadecyloxyand octadecyloxy. An alkoxy may be substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, heteroaryl(alkyl) or heterocyclyl(alkyl)connected, as substituents, via a carbonyl group. Examples includeformyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may besubstituted or unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, l-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aralkyl, (heteroaryl)alkyl or(heterocyclyl)alkyl, as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R^(A))—”group wherein each X is a halogen, and R^(A) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl.

The term “amino” as used herein refers to a “—NH₂” group.

As used herein, the term “hydroxy” refers to a “—OH” group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a “—N₃” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a “C═O” group.

An “S-sulfonamido” group refers to a “—SO₂N(R^(A)R^(B))” group in whichR^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An S-sulfonamido may besubstituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R^(A))—” group in which Rand R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-sulfonamido may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R^(A)R^(B))” group in whichR^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An O-carbamyl may besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R^(A))—” group in which Rand R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-carbamyl may besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R^(A)R^(B))” group inwhich R^(A) and R^(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aralkyl, (heteroaryl)alkyl or (heterocyclyl)alkyl. An O-thiocarbamyl maybe substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R^(A))—” group in whichR and R^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-thiocarbamyl may besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R^(A)R^(B))” group in which R^(A)and R^(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. A C-amido may be substitutedor unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R^(A))—” group in which R andR^(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl,(heteroaryl)alkyl or (heterocyclyl)alkyl. An N-amido may be substitutedor unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

As used herein, the term “phosphonate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphonate” and “diphosphonate” are usedin their ordinary sense as understood by those skilled in the art, andinclude protonated forms. Additionally, the term “phosphate” is used inits ordinary sense as understood by those skilled in the art, andincludes its protonated forms (for example,

The terms “monophosphate,” “diphosphate,” and “triphosphate” are alsoused in their ordinary sense as understood by those skilled in the art,and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of phosphonates and heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases are intended to be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

As used herein, a “subject” refers to an animal that is a host for aviral infection as described herein. “Animal” includes a mammal.“Mammals” includes, without limitation, mice, rats, rabbits, guineapigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys,chimpanzees, and apes, and, in particular, humans. In a typicalembodiment, the subject is human.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or“therapy” do not necessarily mean total cure or abolition of the diseaseor condition. Any alleviation of any undesired signs or symptoms of adisease or condition, to any extent can be considered treatment and/ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, an effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of an effectiveamount is well within the capability of those skilled in the art, inview of the disclosure provided herein. The effective amount of thecompounds disclosed herein required as a dose will depend on the routeof administration, the type of animal, including human, being treated,and the physical characteristics of the specific animal underconsideration. The dose can be tailored to achieve a desired effect, butwill depend on such factors as weight, diet, concurrent medication andother factors which those skilled in the medical arts will recognize.

Some embodiments disclosed herein include the use of an effective amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the preparation of a medicine for treating a host infectedwith a human papillomavirus, by inhibiting the synthesis of viral DNA.Other embodiments disclosed herein include the use of an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for treating a host infected with a human papillomavirus,wherein the human papillomavirus can be ameliorated by inhibiting thesynthesis of viral DNA. Still other embodiments disclosed herein includea method for treating a host infected with a human papillomavirus thatcan include contacting a cell infected with the human papillomavirus ina subject infected with the human papillomavirus with an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. Yet still other embodiments disclosed herein include amethod for treating a host infected with a human papillomavirus that canincludes administering to a subject infected with the humanpapillomavirus an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, by inhibiting the synthesis ofviral DNA. Some embodiments disclosed herein include compound of Formula(I), or a pharmaceutically acceptable salt thereof, for use treating ahost infected with a human papillomavirus, by inhibiting viralreplication by inhibiting the synthesis of viral DNA.

In some embodiments, the human papillomavirus can be a high-risk humanpapillomavirus, such as those described herein. For example, thehigh-risk human papillomavirus can be selected from HPV-16, HPV-18,HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58,HPV-59, HPV-68, HPV-73 and HPV-82. In some embodiments, the humanpapillomavirus can be HPV-16. In some embodiments, the humanpapillomavirus can be HPV-18. In some embodiments, the humanpapillomavirus can be one or more of the following high-risk types:HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58,HPV-59, HPV-68, HPV-73 and HPV-82. As described herein, the presence ofa HPV infection can be detected using a PAP smear and/or DNA probetesting (for example, HPV DNA probe testing for one or more high-riskHPV types). Therefore, in some embodiments, an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be provided to a subject diagnosed with a HPV infection, for examplea high-risk HPV infection, by a DNA test, such as one of the HPV DNAtests described herein.

In some embodiments, the human papillomavirus can be a low-risk humanpapillomavirus, including those described herein. In some embodiments,the human papillomavirus can be HPV-6. In some embodiments, the humanpapillomavirus can be HPV-11.

A compound of Formula (I), or a pharmaceutically acceptable saltthereof, can be used to treat a host infected with one or more types ofhuman papillomaviruses. For example, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be used to treat HPV-16and HPV-18. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be used to treat bothhigh-risk and low-risk HPV.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.For a topical or intravaginal administration, the dose may be between0.02 mg to 200 mg. The dosage may be a single one or a series of two ormore given in the course of one or more days, as is needed by thesubject. In some embodiments, the compounds will be administered for aperiod of continuous therapy, for example for a week or more, or formonths or years. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered lessfrequently compared to the frequency of administration of another agent.In some embodiments, the total time of the treatment regime with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can less compared to the total time of the treatment regime with anotheragent.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

As described herein, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can have a moiety(ies) that neutralize thecharge of the phosphonate. By neutralizing the charge on thephosphonate, penetration of the cell membrane may be facilitated as aresult of the increased lipophilicity of the compound. Once absorbed andtaken inside the cell, the groups attached to the phosphorus can beeasily removed by esterases, proteases and/or other enzymes. In someembodiments, the groups attached to the phosphorus can be removed bysimple hydrolysis. Inside the cell, the phosphonate thus released maythen be metabolized by cellular enzymes to the monophosphate or to thediphosphate, the active metabolite. Furthermore, in some embodiments,varying the substituents on a compound described herein, such as acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can help maintain the efficacy of the compound by reducing undesirableeffects, such as isomerization.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can act as a chain terminator of DNA synthesis.Once the compound is incorporated into a DNA chain, no furtherelongation is observed to occur. In some embodiments, a compound ofFormula (I) or a pharmaceutically acceptable salt thereof, ismetabolized such that the groups attached to the phosphorus atom areremoved to generate a phosphonic acid. The phosphonic acid can then beanabolized to a diphosphate, the active metabolite, that can act as achain terminator of DNA synthesis. Once the compound is incorporatedinto a DNA chain, no further elongation is observed to occur.

Additionally, in some embodiments, the presence of a moiety(ies) thatneutralizes the charge of the phosphonate can increase the stability ofthe compound by inhibiting its degradation. Also, in some embodiments,the presence of a moiety(ies) that neutralizes the charge of thephosphonate can make the compound more resistant to cleavage in vivo andprovide sustained, extended efficacy. In some embodiments, a moiety(ies)that neutralizes the charge of the phosphonate can facilitate thepenetration of the cell membrane by a compound of Formula (I) by makingthe compound more lipophilic. In some embodiments, a moiety(ies) thatneutralizes the charge of the phosphonate can have improved oralbioavailability, improved aqueous stability and/or reduced risk ofbyproduct-related toxicity.

Compounds

In a first embodiment disclosed herein are a compound of Formula (I), ora pharmaceutically acceptable salt thereof:

wherein: B¹ is a naturally occurring purine, a naturally occurringpyrimidine, a non-naturally occurring purine or a non-naturallyoccurring pyrimidine. The term naturally occurring purine or pyrimidinebase includes guanine, adenine, hypoxanthine, xanthine, theobromine,caffeine, uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine oruracil, wherein the acyclic chain is bonded to the N as normallyoccurring in nature. Attachment of the naturally occurring purine orpyrimidine base can be at any available site, e.g., guanin-9-yl,guanine-7-yl, adenine-9-yl, cytosine-1-yl, thymin-1-yl, uracil-1-yl,2,6-diaminopurin-9-yl. The term “non-naturally occurring” purine orpyrimidine refers to purine or pyrimidine not found in nature, forexample, 5-fluorouracil, 5-fluorocytosine, 7-deazaguanine and9-deazaguanine.

In nonlimiting embodiments, B¹ can be:

wherein R¹³ can be an unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆cycloalkyl. In some embodiments, R¹³ can be methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched or straightchained) or hexyl (branched or straight chained). In other embodiments,R¹³ can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In otherembodiments, B¹ can be adenine, cytosine, thymine, uracil,2,6-diaminopurine, 7-deazapurine or 9-deazapurine. Z¹ and Z² can beindependently O (oxygen) or NR^(Z), wherein R^(Z) can be H (hydrogen) oran optionally substituted C₁₋₄ alkyl; wherein when Z¹ and Z² are eachindependently O (oxygen); R¹ can be selected from, an optionallysubstituted —C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄ alkynyl, anoptionally substituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkyl(C₁-C₄alkyl)-, an optionally substituted cycloalkenyl, an optionallysubstituted cycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl,an optionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-,

R² can be selected from, an optionally substituted —C₂₋₂₄ alkenyl, anoptionally substituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or when Z¹ and Z² are each independently O; R¹ and R² can be takentogether to form a moiety selected from an optionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; or one of Z¹ and Z² can beindependently O (oxygen) and the other Z¹ or Z² group is NR^(Z), whereinR^(Z) can be H (hydrogen) or an optionally substituted C₁₋₄ alkyl; or Z¹and Z² are each NR^(Z), wherein R^(Z) can be H (hydrogen) or anoptionally substituted C₁₋₄ alkyl; wherein: R¹ and R² can each beindependently selected from an optionally substituted —C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄alkynyl, an optionally substituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionallysubstituted —(CHR⁴)_(b)—O—C₂₋₂₄ alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkyl(C₁-C₄ alkyl)-, anoptionally substituted cycloalkenyl, an optionally substitutedcycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl, asubstituted aryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, anoptionally substituted heteroaryl(C₁-C₄ alkyl)-, an optionallysubstituted heterocyclyl, an optionally substituted heterocyclyl(C₁-C₄alkyl)-,

or when one of Z¹ or Z² is O; and the other Z¹ or Z² group is NR^(Z) orboth of Z¹ and Z² is NR^(Z); R¹ and R² can be taken together to form amoiety selected from an optionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ can be selected fromhydrogen, optionally substituted alkyl such as CH₃, CH₂OH, CH₂F, CHF₂,CF₃, or optionally substituted heteroalkyl such as OCH₃; each R⁴ can beindependently hydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A);each R^(4A) can be hydrogen, an optionally substituted C₁₋₂₄ alkyl or anoptionally substituted aryl; each R⁵, each R⁶ and each R⁸ can beindependently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰can be independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ can be independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;each a and each b can be independently 1, 2, 3 or 4; each c and each dcan be independently 0, 1, 2 or 3.

In embodiments, when B¹ is

R³ can be selected from optionally substituted alkyl such as CH₃, CH₂OH,CH₂F, CHF₂, CF₃, or optionally substituted heteroalkyl such as OCH₃.

In embodiments, compounds are disclosed having Formula Ia:

wherein: R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl),cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; p=1, 2, 3, 4 or 5; and B¹ and R³ are asdefined above.

In embodiments, compounds are disclosed having Formula Ib:

wherein: B¹, R³, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ic:

wherein: B¹, R³, R⁵, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Id:

wherein: B¹, R³, R⁶, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ie:

wherein: B¹, R³, R⁷, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula If:

wherein: B¹, R³, R⁸, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ig:

wherein: B¹, R³, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ih:

wherein: B¹, R³, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ii:

wherein: B¹, R³, R⁹R¹⁰, R¹¹, R¹² and p are as defined above.

In embodiments, compounds are disclosed having Formula Ij:

wherein: B¹, R³, and R⁸ are as defined above.

In embodiments, compounds are disclosed having Formula Ik:

wherein: B¹ and R³ are as defined above.

In embodiments, compounds are disclosed having Formula Il:

wherein: B¹, R³, R¹² and p are as defined above.

In an alternate embodiment, compounds are disclosed having Formula Im:

wherein: B¹, R³, R¹² and p are as defined above.

Some embodiments of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are provided in Table 1. In Table 1,

TABLE 1 B¹ Z¹ Z² R¹ R² G1 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G1 O O—C₂₋₂₄ alkynyl —C₁₂₋₂₄ alkenyl G1 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄alkenyl G1 O O Cycloalkyl —C₁₂₋₂₄ alkenyl G1 O O cycloalkyl(C₁₋₄ alkyl)-—C₁₂₋₂₄ alkenyl G1 O O Cycloalkenyl —C₁₂₋₂₄ alkenyl G1 O Ocycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄ alkenyl G1 O O Aryl —C₁₂₋₂₄ alkenyl G1O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄ alkenyl G1 O O Heteroaryl —C₁₂₋₂₄ alkenylG1 O O heteroaryl(C₁₋₄ alkyl) —C₁₂₋₂₄ alkenyl G1 O O —C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O —C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G1 OO —(CH₂)₂O—C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O Cycloalkyl—(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O cycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄alkenyl G1 O O Cycloalkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G1 O Ocycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O Aryl—(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O aryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G1O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G1 O heteroaryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G1 O O

G1 O O

G1 O O

G1 O O

G1 NCH₃ O —(CH₂)₃CH₂Cl

G1 ++ O —(CH₂)₃CH₂Cl

G1 O O

G1 O O

G2 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G2 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G2 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G2 O O Cycloalkyl—C₁₂₋₂₄ alkenyl G2 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G2 O OCycloalkenyl —C₁₂₋₂₄ alkenyl G2 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G2 O O Aryl —C₁₂₋₂₄ alkenyl G2 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G2 O O Heteroaryl —C₁₂₋₂₄ alkenyl G2 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G2 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O—C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O Cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O Cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G2 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G2 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G2 O O

G2 O O

G2 O O

G2 O O

G2 NCH₃ O —(CH₂)₃CH₂Cl

G2 ++ O —(CH₂)₃CH₂Cl

G2 O O

G2 O O

G3 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G3 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G3 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G3 O O Cycloalkyl—C₁₂₋₂₄ alkenyl G3 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G3 O OCycloalkenyl —C₁₂₋₂₄ alkenyl G3 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G3 O O Aryl —C₁₂₋₂₄ alkenyl G3 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G3 O O Heteroaryl —C₁₂₋₂₄ alkenyl G3 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G3 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O—C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O Cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O Cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G3 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G3 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G3 O O

G3 O O

G3 O O

G3 O O

G3 NCH₃ O —(CH₂)₃CH₂Cl

G3 ++ O —(CH₂)₃CH₂Cl

G3 O O

G3 O O

G4 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G4 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G4 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G4 O O Cycloalkyl—C₁₂₋₂₄ alkenyl G4 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G4 O OCycloalkenyl —C₁₂₋₂₄ alkenyl G4 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G4 O O Aryl —C₁₂₋₂₄ alkenyl G4 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G4 O O Heteroaryl —C₁₂₋₂₄ alkenyl G4 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G4 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O—C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O Cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G4 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G4 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G4 O O

G4 O O

G4 O O

G4 O O

G4 NCH₃ O —(CH₂)₃CH₂Cl

G4 ++ O —(CH₂)₃CH₂Cl

G4 O O

G4 O O

G5 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G5 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G5 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G5 O O cycloalkyl—C₁₂₋₂₄ alkenyl G5 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G5 O Ocycloalkenyl —C₁₂₋₂₄ alkenyl G5 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G5 O O Aryl —C₁₂₋₂₄ alkenyl G5 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G5 O O Heteroaryl —C₁₂₋₂₄ alkenyl G5 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G5 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O—C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G5 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G5 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G5 O O

G5 O O

G5 O O

G5 O O

G5 NCH₃ O —(CH₂)₃CH₂Cl

G5 ++ O —(CH₂)₃CH₂Cl

G5 O O

G5 O O

G6 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G6 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G6 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G6 O O cycloalkyl—C₁₂₋₂₄ alkenyl G6 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G6 O Ocycloalkenyl —C₁₂₋₂₄ alkenyl G6 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G6 O O Aryl —C₁₂₋₂₄ alkenyl G6 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G6 O O Heteroaryl —C₁₂₋₂₄ alkenyl G6 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G6 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O—C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G6 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G6 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G6 O O

G6 O O

G6 O O

G6 O O

G6 NCH₃ O —(CH₂)₃CH₂Cl

G6 ++ O —(CH₂)₃CH₂Cl

G6 O O

G6 O O

G7 O O —C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G7 O O —C₂₋₂₄ alkynyl —C₁₂₋₂₄alkenyl G7 O O —(CH₂)₂O—C₂₋₂₄ alkenyl —C₁₂₋₂₄ alkenyl G7 O O cycloalkyl—C₁₂₋₂₄ alkenyl G7 O O cycloalkyl(C₁₋₄ alkyl)- —C₁₂₋₂₄ alkenyl G7 O Ocycloalkenyl —C₁₂₋₂₄ alkenyl G7 O O cycloalkenyl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G7 O O Aryl —C₁₂₋₂₄ alkenyl G7 O O aryl(C₁₋₄ alkyl) —C₁₂₋₂₄alkenyl G7 O O Heteroaryl —C₁₂₋₂₄ alkenyl G7 O O heteroaryl(C₁₋₄ alkyl)—C₁₂₋₂₄ alkenyl G7 O O —C₂₋₂₄ alkenyl —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O—C₂₋₂₄ alkynyl —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O —(CH₂)₂O—C₂₋₂₄ alkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O cycloalkyl —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O Ocycloalkyl(C₁₋₄ alkyl)- —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O cycloalkenyl—(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O cycloalkenyl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄alkenyl G7 O O Aryl —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O aryl(C₁₋₄ alkyl)—(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O Heteroaryl —(CH₂)₂O—C₂₋₂₄ alkenyl G7 Oheteroaryl(C₁₋₄ alkyl) —(CH₂)₂O—C₂₋₂₄ alkenyl G7 O O

G7 O O

G7 O O

G7 O O

G7 NCH₃ O —(CH₂)₃CH₂Cl

G7 ++ O —(CH₂)₃CH₂Cl

G7 O O

G7 O O

++ = N(CH₂)—CH(OH)—CH₂OH

In an alternate embodiment, in Table 1, when the base is G1 or G2, R³can be selected from optionally substituted alkyl such as CH₃, CH₂OH,CH₂F, CHF₂, CF₃, or optionally substituted heteroalkyl such as OCH₃. InTable 1, C₂₋₂₄ alkenyl, —(CIH₂)₂O—C₂₋₂₄ alkenyl, aryl (includingphenyl), aryl(C₁₋₄ alkyl) (including benzyl),

can be each optionally substituted. R¹³ is C₁₋₆ alkyl or cycloalkyl(C₀₋₄alkyl).

In some embodiments, at least one of R¹ and R² can be an optionallysubstituted C₂₋₂₄ alkenyl. In still other embodiments, R¹ and R² bothcan be an optionally substituted C₂₋₂₄ alkenyl. When one or both of R¹and R² is an optionally substituted C₂₋₂₄ alkenyl, the optionallysubstituted C₂₋₂₄ alkenyl can be the aliphatic chain from a fatty acid.Fatty acid aliphatic chains differ by length. Types of fatty acidsinclude short-chain fatty acids (fewer than six carbons), medium-chainfatty acids (six to twelve carbons), long-chain fatty acids (thirteen totwenty-one carbons), and very long-chain fatty acids (more thantwenty-two carbons). Examples of aliphatic chains include, but are notlimited to, the following: myristoleyl, myristyl, palmitoleyl, palmityl,sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl,eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl,stearyl, arachidyl, behenyl, lignoceryl and cerotyl. In some embodimentsof this paragraph, at least one of Z¹ and Z² can be O. In someembodiments of this paragraph, both Z¹ and Z² can be O.

In some embodiments, at least one of R¹ and R² can be—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl. In other embodiments, R¹ and R² both can be—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl. In some embodiments, each R⁴ can behydrogen. In some embodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄alkyl. In some embodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A).In some embodiments, b can be 1. In other embodiments, b can be 2. Instill other embodiments, b can be 3. In yet still other embodiments, bcan be 4. In some embodiments of this paragraph, at least one of Z¹ andZ² can be O. In some embodiments of this paragraph, both Z¹ and Z² canbe O.

When an R⁴ moiety is present, in some embodiments, R^(4A) can be H(hydrogen). In other embodiments, R^(4A) can be an optionallysubstituted C₁₋₂₄ alkyl. In still other embodiments, R^(4A) can be anoptionally substituted aryl. In embodiments, at least one R⁴ can be—(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c can be 0. In other embodiments, at leastone R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c can be 1. In still otherembodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c canbe 2. In yet still other embodiments, at least one R⁴ can be—(CH₂)_(c)—S—C₁₋₂₄ alkyl, and c can be 3. In embodiments, at least oneR⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 0. In other embodiments, atleast one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 1. In still otherembodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A), and d can be 2.In yet still other embodiments, at least one R⁴ can be—O—(CH₂)_(d)—R^(4A), and d can be 3. When more than one R⁴ is present,the R⁴ moieties can be the same, or at least one R⁴ can be different.

In embodiments, at least one of R¹ and R² can be an optionallysubstituted aryl(C₁₋₄ alkyl). In other embodiments, R¹ and R² both canbe an optionally substituted aryl(C₁₋₄ alkyl). A suitable optionallysubstituted aryl(C₁₋₄ alkyl) is an optionally substituted benzyl. Whenthe aryl and/or aryl(C₁₋₄ alkyl) is substituted, the aryl ring can besubstituted with 1, 2, 3 or more than 3 substituents. When more than twosubstituents are present, the substituents can be the same or different.In embodiments, the aryl ring can be a para-, ortho- or meta-substitutedphenyl. In some embodiments of this paragraph, at least one of Z¹ and Z²can be O. In some embodiments of this paragraph, both Z¹ and Z² can beO.

In embodiments, at least one of R¹ and R² can be

or one of R¹ and R² can be

In other embodiments, R¹ and R² both can be

In embodiments, R⁵ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁵ can be an unsubstituted C₁₋₆ alkyl. In otherembodiments, R⁵ can be an optionally substituted C₂₋₈ alkenyl, such asan optionally substituted allyl. In still other embodiments, R⁵ can bean optionally substituted cycloalkyl, for example, an optionallysubstituted C₃₋₆ cycloalkyl or an optionally substituted C₅₋₆cycloalkyl. In yet still other embodiments, R⁵ can be an optionallysubstituted aryl, such as an optionally substituted phenyl. Inembodiments, R⁶ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁶ can be an unsubstituted C₁₋₆ alkyl. In otherembodiments, R⁶ can be an optionally substituted C₂₋₈ alkenyl. In stillother embodiments, R⁶ can be an optionally substituted cycloalkyl. Inyet still other embodiments, R⁶ can be an optionally substituted aryl,such as an optionally substituted phenyl. Examples of suitable R⁶ groupsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, tert-butyl, pentyl (branched or straight chained),hexyl (branched or straight chained), an optionally substituted allyl,an optionally substituted C₃₋₆ cycloalkyl, an optionally substitutedC₅₋₆ cycloalkyl and an optionally substituted phenyl. In someembodiments of this paragraph, at least one of Z¹ and Z² can be O. Insome embodiments of this paragraph, both Z¹ and Z² can be O. Inembodiments, one of R¹ and R² can be isopropyloxycarbonyloxymethyl(POC).

In embodiments, at least one of R¹ and R² can be

In other embodiments, R¹ and R² both can be

In still other embodiments, R¹ and R² both can be

In embodiments, R⁸ can be an optionally substituted C₁₋₈ alkyl. Inembodiments, R⁸ can be an unsubstituted C₁₋₆ alkyl. In otherembodiments, R⁸ can be an optionally substituted C₂₋₅ alkenyl, such asan optionally substituted allyl. In still other embodiments, R⁸ can bean optionally substituted cycloalkyl, for example, an optionallysubstituted C₃₋₆ cycloalkyl or an optionally substituted C₅₋₆cycloalkyl. In yet still other embodiments, R⁸ can be an optionallysubstituted aryl, such as an optionally substituted phenyl. In someembodiments of this paragraph, at least one of Z¹ and Z² can be O. Insome embodiments of this paragraph, both Z¹ and Z² can be O. Inembodiments, R¹ and R² both can be an S-acylthioethyl (SATE) group andform a SATE ester prodrug. In other embodiments, R¹ and R² both can be aS-[(2-hydroxyethyl)sulfidyl]-2-thioethyl (DTE) group and form a DTEester prodrug. In still other embodiments, one of R¹ and R² can be aS-acylthioethyl (SATE) group, and the other of R¹ and R² can be anoptionally substituted phenyl group and form a phenyl(SATE) prodrug. Inyet still other embodiments, one of R¹ and R² can be a S-acylthioethyl(SATE) group, and the other of R¹ and R² can be an N-linked alpha-aminoacid ester and form a (SATE)-phosphonoamidate diester prodrug.

The term “N-linked alpha-amino acid ester” refers to an amino acid thatis attached to the indicated moiety via a main-chain amino ormono-substituted amino group and wherein the main-chain carboxylic acidgroup has been converted to an ester group. Examples of alpha-aminoacids include, but are not limited to, alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan and valine. When the amino acid isattached in an —N-linked amino acid, one of the hydrogens that is partof the main-chain amino or mono-substituted amino group is not presentand the amino acid is attached via the nitrogen. In embodiments, theester group has a formula selected from alkyl-O—C(═O)—,cycloalkyl-O—C(═O)—, aryl-O—C(═O)— and aryl(alkyl)-O—C(═O)—. N-linkedalpha-amino acid esters can be substituted or unsubstituted. When R¹and/or R² is an N-linked alpha-amino acid ester, the main-chain nitrogenof the main-chain amino or mono-substituted amino group is the nitrogenof Z¹ and/or Z², respectively.

In embodiments, at least one of R¹ and R² can be

In other embodiments, R¹ and R² both can be

In embodiments, R can be hydrogen. In other embodiments, R⁷ can be anoptionally substituted C₁₋₈ alkyl. In embodiments, R⁷ can be a C₁₋₄alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyland t-butyl. In still other embodiments, R⁷ can be an optionallysubstituted cycloalkyl, for example, an optionally substituted C₃₋₆cycloalkyl or an optionally substituted C₅₋₆ cycloalkyl. In yet stillother embodiments, R⁷ can be an optionally substituted aryl, such as anoptionally substituted phenyl or an optionally substituted naphthyl. Insome embodiments of this paragraph, at least one of Z¹ and Z² can be O.In some embodiments of this paragraph, both Z¹ and Z² can be O. Inembodiments, R¹ and R² both can be a dioxolenone group and form adioxolenone prodrug.

In embodiments, R¹ and R² can be taken together to form an optionallysubstituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered ring system, and the indicate the points of attachment toZ¹ and Z², respectively. An example of R¹ and R² taken together to forman optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered ring system is the following:

(Ph is an optionally substituted phenyl).When substituted, the ring of

can be substituted 1, 2, 3 or 3 or more times. When substituted withmultiple substituents, the substituents can be the same or different. Inembodiments, the

ring can be substituted with an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substitutedheterocyclyl. In embodiments, R¹ and R² can be taken together to form anoptionally substituted

such as

wherein R^(A) can be an optionally substituted phenyl, an optionallysubstituted mono-cyclic heteroaryl (such as pyridinyl) or an optionallysubstituted mono-cyclic heterocyclyl. In embodiments, R^(6A) and R^(7A)can form a cyclic 1-aryl-1,3-propanyl ester (HEPDIRECT™) prodrug moiety.

In embodiments, R¹ and R² can be taken together to form an optionallysubstituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form aten-membered ring system, and the indicate the points of attachment toZ¹ and Z², respectively. Example of an optionally substituted

include

In embodiments, R¹ and R² can form a cyclosaligenyl (cycloSal) prodrug.An example of R¹ and R² taken together to form an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form aten-membered ring system is the following:

In embodiments, one of R¹ or R² can be

wherein Z¹ can be NR^(Z), such as NH. In embodiments, R⁹ can behydrogen. In other embodiments, R⁹ can be an optionally substituted C₁₋₆alkyl. In embodiments, R¹⁰ can be hydrogen. In other embodiments, R¹⁰can be an unsubstituted C₁₋₆ alkyl, —CH₂SH, —CH₂(C═O)NH₂,—CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionally substituted phenyl,—CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

or —(CH₂)₄NH₂. In embodiments, R¹¹ can be hydrogen. In embodiments, R¹¹can be an optionally substituted C₁₋₈ alkyl. In still other embodiments,R¹¹ can be an optionally substituted cycloalkyl, such as an optionallysubstituted C₃₋₆ cycloalkyl. In yet still other embodiments, R¹¹ can bean optionally substituted aryl. For example, R¹¹ can be a substituted orunsubstituted phenyl. In embodiments, R¹¹ can be an optionallysubstituted aryl(C₁₋₆ alkyl) (such as an optionally substituted benzyl).

When Z¹ and R¹ or Z² and R² form

can be N-linked alpha-amino acid ester. N-linked alpha-amino acid estersare described herein. In embodiments,

In other embodiments,

In embodiments, R can be

wherein Z¹ can be NH; and R² can be an optionally substituted aryl(C₁₋₄alkyl) (for example, an optionally substituted benzyl), and form anoptionally substituted benzyl phosphonoamidate prodrug.

When Z¹ or Z² is NR^(Z), R^(Z) can be H (hydrogen) or an optionallysubstituted C₁₋₄ alkyl. In embodiments, Z¹ or Z² can be NH. In otherembodiments, Z¹ or Z² can be N-an optionally substituted C₁₋₄ alkyl. Inembodiments, Z¹ or Z² can be N-an unsubstituted C₁₋₄ alkyl. For example,Z¹ or Z² can be N-methyl, N-ethyl, N-(n-propyl), N-(iso-propyl),N-(n-butyl), N-(iso-butyl) or N-(t-butyl). In embodiments, the N-anoptionally substituted C₁₋₄ alkyl can be —N(CH₂)—CH(OH)—CH₂OH.

In embodiments, at least one of R¹ and R² can be

In other embodiments, R¹ and R² both can be

In embodiments, one of R¹ and R² can be

and the other of R¹ and R² can be an optionally substituted C₂₋₂₄alkenyl. In some embodiments of this paragraph, at least one of Z¹ andZ² can be O. In some embodiments of this paragraph, both Z¹ and Z² canbe O. In some embodiments of this paragraph, one of Z¹ and Z² can be Qand the other of Z¹ and Z² can be NR^(Z). Examples of prodrugs thatinclude

include the following:

In embodiments, a compound of Formula (I) can be a nitrofuranylmethylphosphonoamidate prodrug, wherein R¹ can be

R² can be —(CH₂)₃CH₂Cl, Z¹ can be O, and Z² can be NCH₃. In embodiments,a compound of Formula (I) can be a nitrofuranylmethyl N-dihydroxypropylphosphonoamidate prodrug, wherein R¹ can be

R² can be —(CH₂)₃CH₂Cl, Z¹ can be O, and Z² can be —N(CH₂)—CH(OH)—CH₂OH.

In embodiments, R¹ and R² can be the same. In embodiments, R¹ and R² canbe different.

In a second embodiment disclosed herein are compound of Formula (I), ora pharmaceutically acceptable salt thereof:

wherein: B¹ is as defined above; Z¹ and Z² can be independently O(oxygen) or NR^(Z), wherein R^(Z) can be H (hydrogen) or an optionallysubstituted C₁₋₄ alkyl; R¹ can be selected from an optionallysubstituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄ alkenyl, anoptionally substituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionallysubstituted —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted aryl,an optionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heterocyclyl,

R² can selected from an optionally substituted-C₁₋₂₄ alkyl, anoptionally substituted —C₂₋₂₄ alkenyl, an optionally substituted—(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, an optionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄alkenyl, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl),

or Z¹ and Z² can be O; and R¹ and R² can be taken together to form amoiety selected from an optionally substituted

and an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; each R⁴ can be independently H(hydrogen), —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A)can be H (hydrogen), an optionally substituted C₁₋₂₄ alkyl or anoptionally substituted aryl; each R⁵, each R⁶ and each R⁸ can beindependently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₅ alkenyl, an optionally substituted cycloalkyl or anoptionally substituted aryl; each R⁹ can be independently H (hydrogen)or an optionally substituted C₁₋₆ alkyl.

In embodiments, R¹ can be absent or H; and R² can be selected from anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR⁴)_(a)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

In embodiments, R¹ and R² can be independently selected from anoptionally substituted —C₁₋₂₄ alkyl, an optionally substituted —C₂₋₂₄alkenyl, an optionally substituted —(CHR⁴)_(b)—O—C₁₋₂₄ alkyl, anoptionally substituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl),

In embodiments, at least one of R and R can be an optionally substitutedC₁₋₂₄ alkyl or an optionally substituted C₂₋₂₄ alkenyl. In otherembodiments, R¹ and R² both can be an optionally substituted C₁₋₂₄alkyl. In still other embodiments, R¹ and R² both can be an optionallysubstituted C₂₋₂₄ alkenyl. When one or both of R¹ and R² is anoptionally substituted C₁₋₂₄ alkyl or an optionally substituted C₂₋₂₄alkenyl, the optionally substituted C₁₋₂₄ alkyl and/or the optionallysubstituted C₂₋₂₄ alkenyl can be the aliphatic chain from a fatty acid.Fatty acid aliphatic chains differ by length. Types of fatty acidsinclude short-chain fatty acids (fewer than six carbons), medium-chainfatty acids (six to twelve carbons), long-chain fatty acids (thirteen totwenty-one carbons), and very long-chain fatty acids (more thantwenty-two carbons). Examples of aliphatic chains include, but are notlimited to, the following: myristoleyl, myristyl, palmitoleyl, palmityl,sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl,eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl,stearyl, arachidyl, behenyl, lignoceryl and cerotyl. In some embodimentsof this paragraph, at least one of Z¹ and Z² can be O. In someembodiments of this paragraph, both Z¹ and Z² can be O.

In embodiments, at least one of R¹ and R² can be —(CHR⁴)_(a)—O—C₁₋₂₄alkyl. In other embodiments, R¹ and R² both can be —(CHR⁴)_(a)—O—C₁₋₂₄alkyl. In some embodiments, each R⁴ can be hydrogen. In someembodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄ alkyl. In someembodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A). In someembodiments, a can be 1. In other embodiments, a can be 2. In stillother embodiments, a can be 3. In yet still other embodiments, a can be4. In some embodiments of this paragraph, at least one of Z¹ and Z² canbe O. In some embodiments of this paragraph, both Z¹ and Z² can be O.

In some embodiments, at least one of R¹ and R² can be—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl. In other embodiments, R¹ and R² both can be—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl. In some embodiments, each R⁴ can behydrogen. In some embodiments, at least one R⁴ can be —(CH₂)_(c)—S—C₁₋₂₄alkyl. In some embodiments, at least one R⁴ can be —O—(CH₂)_(d)—R^(4A).In some embodiments, b can be 1. In other embodiments, b can be 2. Instill other embodiments, b can be 3. In yet still other embodiments, bcan be 4. In some embodiments of this paragraph, at least one of Z¹ andZ² can be O. In some embodiments of this paragraph, both Z¹ and Z² canbe O.

In some embodiments, at least one of R¹ and R² can be an optionallysubstituted aryl. In other embodiments, R¹ and R² both can be anoptionally substituted aryl. For example, one or both R¹ and R² can bean optionally substituted phenyl. In some embodiments, at least one ofR¹ and R² can be an optionally substituted aryl(C₁₋₄ alkyl). In otherembodiments, R¹ and R² both can be an optionally substituted aryl(C₁₋₄alkyl). A suitable optionally substituted aryl(C₁₋₄ alkyl) is anoptionally substituted benzyl. When the aryl and/or aryl(C₁₋₄ alkyl) issubstituted, the aryl ring can be substituted with 1, 2, 3 or more than3 substituents. When more than two substituents are present, thesubstituents can be the same or different. In some embodiments, the arylring can be a para-, ortho- or meta-substituted phenyl. In someembodiments of this paragraph, at least one of Z¹ and Z² can be O. Insome embodiments of this paragraph, both Z¹ and Z² can be O.

In embodiments, at least one of R¹ and R² can be

In embodiments, R¹ and R² both can be

In embodiments, R¹ and R² both can be a isopropyloxycarbonyloxymethyl(POC) group, and form a bis(isopropyloxycarbonyloxymethyl) (bis(POC))prodrug. In other embodiments, one or both of R¹ and R² can bepivaloyloxymethyl (POM). In some embodiments, R¹ and R² both can be apivaloyloxymethyl (POM) group, and form a bis(pivaloyloxymethyl)(bis(POM)) prodrug.

In embodiments, R¹ and R² both can be aS-[(2-hydroxyethyl)sulfidyl]-2-thioethyl (DTE) group and form a DTEester prodrug. In still other embodiments, one of R¹ and R² can be aS-acylthioethyl (SATE) group, and the other of R¹ and R² can be anoptionally substituted phenyl group and form a phenyl(SATE) prodrug. Inyet still other embodiments, one of R¹ and R² can be a S-acylthioethyl(SATE) group, and the other of R¹ and R² can be an N-linked alpha-aminoacid ester and form a (SATE)-phosphonamidate diester prodrug.

In embodiments, at least R¹ can be

wherein Z¹ can be NR^(Z), such as NH. In other embodiments, R¹ and R²both can be

wherein Z¹ and Z² both can be NR^(Z), such as NH. In some embodiments,R⁹ can be hydrogen. In other embodiments, R⁹ can be an optionallysubstituted C₁₋₆ alkyl.

In embodiments, a compound of Formula (I) can be a phosphorodiamidateprodrug, wherein R¹ and R² both can be

wherein Z¹ and Z² both can be NR^(Z), such as NH.

In embodiments, a compound of Formula (I) can be a nitrofuranylmethylphosphonoamidate prodrug, wherein R¹ can be

R² can be —(CH₂)₃CH₂Cl, Z¹ can be O, and Z² can be NCH₃.

In embodiments, R¹ and R² can be the same. In some embodiments, R¹ andR² can be different.

As described herein, B¹ can be a naturally occurring purine, naturallyoccurring pyrimidine, non-naturally occurring purine or a non-naturallyoccurring pyrimidine. For example, B¹ can be

wherein R can be an unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆cycloalkyl. In some embodiments, R¹³ can be methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched or straightchained) or hexyl (branched or straight chained). In other embodiments,R¹³ can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Examples of compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, include, but are not limited to:

or a pharmaceutically acceptable salt of the foregoing.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, there is provided a compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

In embodiments, compounds have the formula:

wherein R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group. The phenyl ring can be substituted by R¹² 1,2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group. The phenyl ring can be substituted by R¹² 1,2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, compounds have the Formula:

wherein R¹² is defined above. The phenyl ring can be substituted by R¹²1, 2 or 3 times.

In embodiments, R¹² in a structure above is independently selected fromalkyl, alkoxy, halogen and cyano.

In embodiments, R¹ is an optionally substituted heteroaryl, for examplepyridine, pyrimidine, imidazole, pyrrole, furan or thiophene.

In embodiments, R¹ is an optionally substituted aryl include but notlimited to phenyl.

In embodiments, R¹ is optionally substituted aryl(C₁₋₄ alky).

In embodiments, R¹ is an optionally substituted heteroaryl, for examplepyridine, pyrimidine, imidazole, pyrrole, furan or thiophene and R² is—(CHR⁴)_(a)—O—(C₁₋₂₄ alkyl or alkenyl). In some embodiments, R¹ isoptionally substituted aryl including, but not limited, to phenyl and R²is —(CHR⁴)_(a)—O—(C₁₋₂₄ alkyl or alkenyl). In some embodiments, R¹ isoptionally substituted aryl(C₁₋₄ alky) and R² is —(CHR⁴)_(a)—O—(C₁₋₂₄alkyl or alkenyl).

In some embodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot beO and R² cannot be phenyl (a substituted or unsubstituted phenyl). Insome embodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be Oand R² cannot be benzyl (a substituted or unsubstituted benzyl). In someembodiments, when R¹ is —(CH₂)₂—O—(CH₂)₁₇CH₃, then Z² cannot be O and R²cannot be hydrogen. In some embodiments, when R¹ is—(CH₂)₃—O—(CH₂)₁₅CH₃, then Z² cannot be O and R² cannot be phenyl (asubstituted or unsubstituted phenyl). In some embodiments, when R¹ is—(CH₂)₃—O—(CH₂)₁₅CH₃, then Z² cannot be O and R² cannot be benzyl (asubstituted or unsubstituted benzyl). In some embodiments, when R¹ is—(CH₂)₃—O—(CH₂)₁₅CH₃, then Z² cannot be O and R² cannot be hydrogen. Insome embodiments, R¹ cannot be —(CH₂)_(a)—O—C₁₋₂₄ alkyl. In someembodiments, the human papillomavirus cannot be HPV-16 and/or HPV-18. Insome embodiments, the human papillomavirus cannot be HPV-11.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof. In someembodiments, the pharmaceutical composition can include a singlediastereomer of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, (for example, a single diastereomer is presentin the pharmaceutical composition at a concentration of greater than 99%compared to the total concentration of the other diastereomers). Inother embodiments, the pharmaceutical composition can include a mixtureof diastereomers of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, the pharmaceutical composition caninclude a concentration of one diastereomer of >50%, ≥60%, ≥70%, ≥80%,≥90%, ≥95%, or ≥98%, as compared to the total concentration of the otherdiastereomers. In some embodiments, the pharmaceutical compositionincludes a 1:1 mixture of two diastereomers of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration. A pharmaceutical composition is suitable for humanand/or veterinary applications.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal, intravaginal andintraocular injections.

One may also administer the compound in a local rather than systemicmanner, for example, via application of the compound directly to theinfected area. The compound can be administered as a gel, a cream and/ora suppository. In addition, the compound can be administered in a depotor sustained release formulation (for example, as nanoparticles and/oran intravaginal ring). Furthermore, one may administer the compound in atargeted drug delivery system, for example, in a liposome coated with atissue-specific antibody. The liposomes will be targeted to and taken upselectively by the organ.

The compositions may, if desired, be presented in a pack, applicator ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration. The packor dispenser may also be accompanied with a notice associated with thecontainer in form prescribed by a governmental agency regulating themanufacture, use, or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the drug for human orveterinary administration. Such notice, for example, may be the labelingapproved by the U.S. Food and Drug Administration for prescriptiondrugs, or the approved product insert. Compositions that can include acompound described herein formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

Synthesis

Compounds of Formula (I) and those described herein may be prepared invarious ways. General synthetic routes to the compound of Formula (I)and some examples of starting materials used to synthesize compounds ofFormula (I) are shown in Scheme 1 and described herein. The routes shownand described herein are illustrative only and are not intended, nor arethey to be construed, to limit the scope of the claims in any mannerwhatsoever. Those skilled in the art will be able to recognizemodifications of the disclosed syntheses and to devise alternate routesbased on the disclosures herein; all such modifications and alternateroutes are within the scope of the claims.

A shown in Scheme 1, the acyclic nucleoside phosphonate can be coupledwith R¹-LG and then with R²-LG, wherein LG is a suitable leaving group(for example, Cl). Alternatively, the OH groups attached to thephosphorus can be transformed and then replaced with R¹ and R². Forexample, the hydrogens of the OH groups can be transformed to alkalimetal ions, such as Na⁺ (shown as R′ in Scheme 1). Methods for couplingan acyclic nucleoside phosphonate are known to those skilled in the art.For examples, see methods described and referenced in Pradere, U. etal., Chem. Rev., 2014, 114:9154-9218.

An acyclic nucleoside phosphonate can be esterified by methods known toone skilled in the art and then reacted with an amine by methods knownto one skilled in the art to generate a phosphoramidate ester of FormulaI.

An acyclic nucleoside phosphonate can be reacted with an amine bymethods known to one skilled in the art to generate a phosphoramidateand subsequently reacted with an amine by methods known to one skilledin the art to generate a bisphosphoramidate of Formula I.

Compounds of Formula I can be synthesized according to or analogously tothe syntheses shown below. In certain embodiments, the person ofordinary skill in the art can replace guanine with another selected basedescribed herein according to the present invention.

EXAMPLES Example 1.9-[(2-phosphonomethoxy)ethyl]-2-amino-6-chloropurine, Tributylamine Salt(7)

Compound 6 was prepared as shown in Scheme A and converted to thephosphonic acid (6-a) by treatment with bromotrimethylsilane, followedby hydrolysis. The detailed methods are described in Holy, A. et al. J.Med. Chem. (1999) 42(12):2064-2086. To prepare 7, a 1 L flask wasequipped with a magnetic stirrer, a nitrogen inlet, and an additionfunnel. Compound 6-a (18.8 g, 61 mmol) and N,N-DMF (200 mL) were added,and the resulting slurry was stirred. Tributylamine (14.9 mL, 62 mmol)was added dropwise over 15-20 mins. The resulting solution was stirredat ambient temperature for 10 mins. Toluene (470 mL) was added, andstirring was continued for 30-40 mins. Seed crystals (50 mg) of compound7 were added. The mixture was stirred for 5 h, after which theprecipitated solids were filtered. The solids were washed with toluene(150 mL) and dried under vacuum for several hours to give 7 (25.6 g, 85%yield) as an off-white powder. The solid was analyzed by ¹H NMR and ³¹PNMR spectroscopy. ¹H NMR (DMSO-d₆) δ 8.20 (s, 1H), 6.91 (s, 2H), 4.20(t, 2H), 3.81 (t, 2H), 3.45 (d, 2H), 2.73 (m, 2H), 1.51 (m, 2H), 1.26(septet, 2H), 0.87 (t, 3H). The spectra were found to be consistent with7.

Example 2. 9-[(2-phosphonomethoxy)ethyl]guanine (PMEG, 9)

Compound 9 was prepared by acidic hydrolysis of 6 as shown in Scheme B.Compound 6 (4.95 g, 12.6 mmol) was dissolved in 80% aq. CH₃COOH. Themixture was stirred and heated at reflux for 3 h. The mixture was thencooled. The solvent was evaporated under vacuum to give crude 8 as anoff-white powder, which was dried in a vacuum oven at 45° C. Compound 8was dissolved in CH₃CN (30 mL), treated with bromo trimethyl silane(11.6 g, 76 mmol) and stirred overnight. The mixture was evaporatedunder vacuum. Water/crushed ice (50 mL) was added to the residue. Theslurry was stirred for 1 h, and the precipitate was collected byfiltration to provide 9 (PMEG, 3.1 g, 85% yield). Additional details forpreparing PMEG are described in Holy, A. et al. J. Med. Chem. (1999)42(12):2064-2086.

Example 3. Odadecyloxyelhyl PM EG (ODE-PMEG, 11)

Method A: Compound 11 was prepared by esterification of 7 according toScheme C. A 1 L flask was equipped with a magnetic stirrer, thencompound 7 (21.7 g, 44 mmol), 2-octadecyloxyethanol (ODE-OH, 14.2 g, 45mmol) and anhydrous N,N-DMF (300 mL) were added. The mixture was stirredand (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 35 g, 67.5 mmol) was subdivided in five equal portions (7 geach) and each portion was then added at 30 mins intervals. After theaddition of PYBOP®, diisopropylethylamine (DIEA, 5.8 g, 45 mmol) and1-hydroxybenzotriazole (HOBt, 3.0 g, 22.5 mmol) were added. Theresulting mixture was stirred at 22-25° C., and the progress of thereaction was monitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) onsilica gel plates (Analtech, UNIPLATES™ Silica gel G, 250 microns).After the reaction was judged complete (16-20 h), the reaction mixturewas slowly poured into a stirred acidic mixture comprised of conc. HCl(10 mL), water (750 mL) and crushed ice (750 mL). Stirring was continuedfor 10 mins. The precipitated solid was collected by filtration, washedwith cold water (2×100 mL) and dried under vacuum to give crude 10 (32.7g). The crude product was purified by silica gel column chromatographywith elution of the product by CH₂Cl₂:MeOH 90:10 to yield 10 (9.5 g,30.7% yield).

A 1 L reaction flask was equipped with a magnetic stirrer and acondenser. Compound 10 (9.5 g, 13.5 mmol), acetic acid (240 mL) andwater (60 mL) were added. The resulting mixture was stirred and heatedto reflux. The progress of the reaction was monitored by TLC (70:30:3:3CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gel plates (Analtech, UNIPLATES™Silica gel G, 250 microns) using a UV lamp and charring. After thereaction was complete (3.5 h), the reaction mixture was cooled to 5° C.,stirred for 2 h and filtered. The product was dried under vacuum to give11 (7.5 g). The crude product was recrystallized in 80:20isopropanol:water. After treatment with decolorizing carbon, thefiltrate was allowed to cool to room temperature (RT) and then in anice-bath. The precipitated solids were filtered and dried under vacuumto give 11 (6.2 g, 78%) as off-white powder.

Method B: Octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine(ODE-PMEG) was prepared according to the method described in Valiaeva,N. et al.; Antiviral Research (2006) 72:10-19.

Example 4. Benzyl PMEG (Bn-PMEG, 13)

Compound 13 was prepared by esterification of 7 with benzyl alcoholaccording to Scheme D. A 100 mL flask was equipped with a magneticstirrer, then compound 7 (2.0 g, 4 mmol), benzyl alcohol (860 mg, 8mmol) and anhydrous N,N-DMF (30 mL) were added. The mixture was stirred.(Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(PYBOP®, 3.2 g, 6 mmol) was subdivided in five equal portions (640 mgeach) and each portion was then added at 30 mins intervals. After theaddition of PYBOP®, diisopropylethylamine (DIEA, 516 mg, 4 mmol) and1-hydroxybenzotriazole (HOBt, 270 mg, 2 mmol) were added. The reactionmixture was stirred at 22-25° C., and the progress of the reaction wasmonitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gelplates (Analtech, UNIPLATES™ Silica gel G, 250 microns). After thereaction was judged complete (16-20 h), the reaction mixture wasconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography with elution of the product by CH₂Cl₂:MeOH 55:45to yield 12 (840 mg).

A 100 mL reaction flask was equipped with a magnetic stirrer and acondenser. Compound 12 (840 mg), acetic acid (24 mL) and water (6 mL)were added. The resulting mixture was stirred and heated to reflux. Theprogress of the reaction was monitored by TLC (70:30:3:3CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gel plates (Analtech, UNIPLATES™Silica gel G, 250 microns) using a UV lamp and charring. After thereaction was complete (3 h), the reaction mixture was evaporated undervacuum. The product was dried under vacuum to afford 13 (7.5 g). Thecrude product was purified by silica gel column chromatography withelution of the product by CH₂Cl₂:MeOH 50:50 to yield purified 13 (620mg) as an off-white powder. ¹H NMR (400 MHz, CDCl₃+methanol) δ 7.87 (s,1H) 7.20-7.36 (m, 5H) 4.92 (d, J=7.33 Hz, 2H) 4.17 (br. s., 2H) 3.78(br. s., 2H) 3.66 (d, J=8.07 Hz, 2H).

Example 5. 1-O-Octadecyl-2-O-benzyl-sn-glyceryl PMEG (ODBG-PMEG, 14)

ODBG-PMEG was prepared by esterification of 7 with1-O-octadecyl-2-O-benzyl-sn-glycerol (ODBG-OH). A 500 mL flask wasequipped with a magnetic stirrer, then compound 7 (9.0 g, 18.25 mmol),ODBG-OH (20.7 mmol) and anhydrous N,N-DMF (200 mL) were added. Themixture was stirred and (benzotriazol-1-yloxy)-tripyrrolidinophosphoniumhexafluorophosphate (PYBOP®, 15.6 g, 30 mmol) was subdivided in 3 equalportions (5.2 g each) and each portion was then added at 30 minsintervals. After the addition of PYBOP®, diisopropylethylamine (DIEA,2.6 g, 20 mmol) and 1-hydroxybenzotriazole (HOBt, 1.2 g, 9 mmol) wereadded. The reaction mixture was stirred at 22-25° C., and the progressof the reaction was monitored by TLC (70:30:3:3 CHCl₃:MeOH:conc.NH₄OH:H₂O) on silica gel plates (Analtech, UNIPLATES™ Silica gel G, 250microns). After the reaction was judged complete (16-20 h), the reactionmixture was concentrated in vacuo. The crude product was purified bysilica gel column chromatography with elution of the product byCH₂Cl₂:EtOH 80:20 to yield the esterified intermediate (7.5 g, 50%yield).

A 500 mL reaction flask was equipped with a magnetic stirrer and acondenser. The esterified intermediate from the previous step (7.5 g),acetic acid (80 mL) and water (20 mL) were added. The resulting mixturewas stirred and heated to reflux. The progress of the reaction wasmonitored by TLC (70:30:3:3 CHCl₃:MeOH:conc. NH₄OH:H₂O) on silica gelplates (Analtech, UNIPLATES™ Silica gel G, 250 microns) using a UV lampand charring. After the reaction was complete (3 h), the reactionmixture was evaporated under vacuum. The crude product was purified bysilica gel column chromatography with elution of the product byCH₂Cl₂:MeOH 80:20 to yield 14 (5.2 g, 81% yield) as an off-white powder.

Example 6. Acyloxyalkyl ester of 9-[2-(phosphonomethoxy)ethyl]-guanine

Acyloxyalkyl esters of PMEG are prepared using methods similar to thosedescribed by Srivasta, et al. Bioorg. Chem. (1984) 12:118-129 andStarrett et al. J. Med. Chem. (1994) 37 1857-1864. A typical approach tosynthesis is shown in Scheme E.

Example 7. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of9-[2-(phosphonomethoxy)-ethyl]guanine

9-[2-(phosphonomethoxy)ethyl]-guanine (PMEG) is neutralized with a 1Msolution of methanolic tetrabutylammonium bromide in MeOH. The solutionis evaporated and co-distilled with EtOH and toluene. The residue isdissolved in anhydrous DMF and treated with(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide at RT for 4 daysaccording to the procedure for preparing the corresponding adefovirprodrugs (see Tichy et al., Bioorg. & Med. Chem. (2011)19(11):3527-3539.

Example 8. S-acylthioethyl (SATE) Esters of PMEG

The general procedure for the synthesis of (S-acylthioethyl) (SATE)esters of PMEG are shown in Scheme G. Procedures are analogous to thosedescribed for preparing the adefovir SATE esters in Benzaria, S. et al.,J. Med. Chem. (1996) 39(25):4958-4965.

Example 9. bis[S-2-hydroxyethylsulfidyl)-2-thioethyl] Esters of PMEG

Bis[S-2-hydroxyethylsulfidyl)-2-thioethyl] PMEG esters (Scheme H) areprepared following similar procedures provided in Puech, F. et al.Antiviral Research (1993) 22:155-174.

Example 10. Aryl Phosphonoamidate PMEG Prodrugs

Aryl phosphonoamidate PMEG prodrugs are prepared following similarprocedures provided in U.S. Pat. No. 8,088,754. Examples are shownbelow.

Synthesis of9-[2-(phenyloxy-(ethoxy-L-alaninyl))-phosphonomethoxy)ethyl]guanine

To a solution of diisopropyl PMEG (1.0 g, 3 mmol) in dry acetonitrile(30 mL), bromotrimethylsilane (2.3 g, 15 mmol) was added and thereaction was stirred at room temperature overnight. The solvents werethen removed under vacuum. The residue was dissolved in anhydrous Et3N(6 mL) and pyridine (25 mL), L-alanine ethyl ester HCl (0.69 g, 4.5mmol) and phenol (0.42 g, 4.5 mmol) were added. A solution ofAldrithiol-2 (4.0 g, 18 mmol eq) and Ph₃P (4.7 g, 18 mmol) in anhydrouspyridine (30 ml) was added to the reaction. The resulting mixture washeated to 50° C. and stirred for 3 hours. After cooling, the solventswere removed under reduced pressure and the residue was adsorbed onsilica gel. The product was isolated as a mixture of diastereomers byflash chromatography on silica gel eluted with 0 to 5% MeOH indichloromethane (410 mg, 29%). ¹H NMR (DMSO-d₆) δ 10.65 (s, 2H), 7.69(s, 1H), 7.68 (s, 1H), 7.35-7.30 (m, 4H), 7.17-7.11 (m, 6H), 6.52 (s,4H), 5.71 (t, 4H), 5.64 (t, 4H), 4.15-4.11 (m, 2H), 4.03-3.99 (m, 2H),3.91-3.81 (m, 4H), 3.36 (s, 2H), 3.07 (q, 2H), 1.20 (d, 3H), 1.15 (d,3H), 1.13 (t, 6H). MS (ESI) 465.20 [M+H]+, 487.19 [M+Na]+, 509.17M−H+2Na]+.

Example 11. Bis(phosphonoamidate) PMEG Prodrugs

Bis(phosphonoamidate) PMEG prodrugs are prepared following similarprocedures provided in U.S. Pat. No. 8,088,754. Examples are shownbelow.

The compound9-[2-(bis-(ethyloxy-L-alaninyl)-phosphonomethoxy)ethyl]guanine,illustrated above, was prepared as described in Lansa, P. et al.European Journal of Medicinal Chemistry, 2011, 46:3748-3754.

Example 12. Cyclic 1-aryl-1,3-propanyl PMEG Esters

Cyclic 1-aryl-1,3-propanyl PMEG esters are prepared following similarprocedures provided in Reddy, et al., J. Med. Chem. (2008) 51:666-676. Ageneral procedure for preparing cyclic 1-aryl-1,3-propanyl PMEG estersis shown in Scheme I.

Example 13. Cyclosal PMEG Esters

Cyclosal PMEG esters are prepared following similar procedures providedin Meier, C. et al., J. Med. Chem. (2005) 48:8079-8086. A generalprocedure for preparing cyclosal PMEG esters is shown in Scheme J.

Example 14. Nitrofuranylmethyl PMEG prodrugs

Nitrofuranylmethyl phosphonoamidate derivatives of PMEG are synthesizedby sequential esterification of compound 7 with 5-nitrofurfuryl alcoholand N-methyl-N-4-chlorobutylamine as depicted in Scheme K. Thenitrofuranylmethyl group has been shown (Tobias, S. C. et al., Mol.Pharmaceutics (2004) 1:112-116) to be readily taken up by cells, thencleaved intracellularly by a reductase enzyme which, in turn, leads tothe formation of an intermediate chlorobutyl phosphonoamidate.Cyclization of the intermediate by nucleophilic attack of the nitrogenatom forms an N-phosphonotrialkyl ammonium species that can afford theunmasked phosphonate PMEG after hydrolysis.

Example 15. Synthesis of ODE-(4-Me-Bn)-PMEG

ODE-PMEG (150 mg, 0.26 mmol), 4-methylbenzyl alcohol (70 mg, 0.52 mmol)and (1H-bentriazol-1-yloxy)-tripyrrolidinophosphonium hexafluoride(PyBOP, 200 mg, 0.4 mmol) were weighed into a dried 100 mL round bottomflask. Anhydrous N,N-dimethylformamide (5 mL) and diisopropylethylamine(0.1 mL, 0.52 mmol) were then added and the reaction was stirred at roomtemperature for 4 hours. The mixture was then concentrated under vacuumto an oil. The residue was adsorbed on silica gel and the product wasisolated by column chromatography on silica gel (eluant: 0 to 10% MeOHin dichloromethane) to yield ODE-(4-Me-Bn)-PMEG as an off-white waxysolid. (60 mg, 33% yield). ¹H NMR (400 MHz, CDCl₃+methanol-d4) δ 7.64(s, 1H) 7.22-7.28 (m, 2H) 7.15-7.20 (m, 2H) 5.04 (dd, J=8.80, 2.20 Hz,2H) 4.19 (t, J=4.95 Hz, 2H) 4.12 (m, 2H) 3.82-3.87 (m, 2H) 3.55-3.59 (m,2H) 3.43 (t, J=6.60 Hz, 2H) 3.35 (dt, J=3.30, 1.65 Hz, 2H) 2.35 (s, 3H)1.49-1.60 (m, 2H) 1.16-1.37 (m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI):690.67 (M+H)+, 712.53 (M+Na)+, 734.51 (M+2Na—H)+.

Example 16. Synthesis of ODE-(3-F-4-OMe-Bn)-PMEG

ODE-(3-F-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using3-fluoro-4-methoxybenzyl alcohol. The product was obtained as a waxysolid (100 mg, 52%). ¹H NMR (400 MHz, CDCl₃+methanol-d4) δ 7.65 (s, 1H)7.06-7.17 (m, 2H) 6.96-7.05 (m, 1H) 5.00 (dd, J=8.80, 1.83 Hz, 2H) 4.21(t, J=5.13 Hz, 2H) 4.14 (m, 2H) 3.81-3.93 (m, 2H) 3.59 (dd, J=4.95, 3.85Hz, 2H) 3.45 (t, J=6.78 Hz, 2H) 3.35 (s, 3H) 1.49-1.60 (m, 2H) 1.07-1.45(m, 30H) 0.86 (t, J=7 Hz, 3H). MS (ESI): 724.56 (M+H)+, 746.49 (M+Na)+.

Example 17. Synthesis of ODE-(3-Cl-4-OMe-Bn)-PMEG

ODE-(3-Cl-4-OMe-Bn)-PMEG was prepared by the method of Example 4, using3-chloro-4-methoxybenzyl alcohol. The product was obtained as a waxysolid (90 mg, 46%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ ppm 7.66 (s,1H) 7.64-7.68 (m, 1H) 7.38-7.42 (m, 1H) 7.40 (d, J=2.20 Hz, 1H)4.95-5.05 (m, 2H) 4.21 (t, J=5.13 Hz, 2H) 4.11-4.17 (m, 2H) 3.87-3.91(m, 2H) 3.84-3.89 (m, 2H) 3.58 (dd, J=4.95, 3.85 Hz, 2H) 3.44 (t, J=6.60Hz, 2H) 3.35 (s, 3H) 1.51-1.59 (m, 2H) 1.06-1.45 (m, 30H) 0.89 (t, J=7Hz, 3H). MS (ESI): 740.52 (M+H)+, 762.47 (M+Na)+.

Example 18. Synthesis of ODE-(3-F-Bn)-PMEG

ODE-(3-F-Bn)-PMEG was prepared by the method of Example 4, using3-fluorobenzyl alcohol. The product was obtained as an off-white solid(80 mg, 44%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.64 (s, 1H)7.42-7.50 (m, 1H) 7.33-7.40 (m, 1H) 6.97-7.19 (m, 2H) 5.03-5.16 (m, 2H)4.11-4.25 (m, 4H) 3.84-3.95 (m, 2H) 3.55-3.65 (m, 2H) 3.41-3.49 (m, 4H)3.35 (s, 3H) 1.49-1.61 (m, 2H) 1.07-1.39 (m, 30H) 0.88 (t, J=7 Hz, 3H).MS (ESI): 694.45 (M+H)+, 716.44 (M+Na)+, 738.44 (M+2Na—H)+.

Example 19. Synthesis of ODE-(3-Cl-Bn)-PMEG

ODE-(3-Cl-Bn)-PMEG was prepared by the method of Example 4, using3-chlorobenzyl alcohol. The product was obtained as an off-white solid(80 mg, 42%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.63 (s, 1H) 7.45(t, J=6.42 Hz, 1H) 7.23-7.41 (m, 3H) 5.06 (d, J=8.80 Hz, 2H) 4.17-4.21(m, 4H) 3.80-3.94 (m, 4H) 3.59 (d, J=4.77 Hz, 2H) 3.44 (t, J=6.78 Hz,2H) 3.36 (s, 4H) 1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78Hz, 3H). MS (ESI) [M+H]+ 710.46, [M+Na]+732.43.

Example 20. Synthesis of ODE-(3-picolyl)-PMEG

ODE-(3-picolyl)-PMEG was prepared by the method of Example 4, using3-pyridinemethanol. The product was obtained as an off-white solid (110mg, 40%). ¹H NMR (400 MHz, CDCl₃+methanol-d₄) δ 7.60 (s, 1H) 7.40-7.42(m, 1H) 7.23-7.31 (m, 3H) 5.16 (d, J=8.80 Hz, 2H) 4.15-4.20 (m, 4H)3.86-3.95 (m, 4H) 3.56-3.60 (m, 2H) 3.41-3.49 (m, 2H) 3.36 (s, 3H)1.50-1.56 (m, 2H) 1.11-1.24 (m, 30H) 0.88 (t, J=6.78 Hz, 3H). MS (EI):677.46 (M+H)+, 699.47 (M+Na)+, 721.41 (M+2Na—H)+.

Example 21. Low Risk and High Risk HPV Assays

An origin-containing low risk or high risk HPV plasmid wasco-transfected with homologous E1 and E2 protein expression vectors intoHEK 293 cells. At 4 h post-transfection, cells were treated with testcompound dilutions and then incubated for 48 h. HPV origin plasmidreplication was detected after digestion with DpnI and exonuclease IIIto remove unreplicated transfected plasmids. Remaining replicated DNAwas quantified by quantitative real time PCR (qPCR). In a parallelexperiment in uninfected cells cytotoxicity was determined by trypanblue exclusion or CELLTITER-GLO® to find the concentration that reducedviable cell number by 50% (CC50). CC₅₀ values were determined by trypanblue exclusion or CELLTITER-GLO® and the selectivity index calculated(Selectivity index=CC₅₀/EC₅₀). The low risk HPV tested was HPV-11, andthe high-risk HPV tested was HPV-16 and HPV-18.

The results are provided in Table A and Table B. As shown in Table A,compounds of Formula (I) are active against both low-risk and high-riskHPV.

TABLE A Compound Low Risk High Risk PMEG C C ODE-PMEG A A ODBG-PMEG B B

-   -   ‘A’ indicates an EC₅₀<0.3 μM, ‘B’ indicates an EC₅₀ of ≥0.3 μM        and <3.0 μM and ‘C’ indicates an EC₅₀≥3.0 μM and <30 μM. For all        the tested compounds, the selectivity indexes were >10.

The results are provided in Table B. As shown in Table B, compounds ofFormula (I) are active against both low-risk and high-risk HPV.

TABLE B Antiviral Activity against HPV-11 in HEK-293 Cells EC₅₀ EC₉₀CC₅₀ Compound (μM) (μM) (μM) SI₅₀ ODE-(4-Me-Bn)-PMEG 0.93 ± 0.91  7.0 ±3.45 23.80 ± 19.52 26 ODE-(3-F-4-OMe-Bn)- 0.18 ± 0.04 0.99 ± 0.13 14.25± 9.48  79 PMEG ODE-(3-Cl-4-OMe Bn)- 0.68 ± 0.62 1.34 ± 0.78 8.31 ± 1.8312 PMEG ODE-(3-F-Bn)-PMEG 0.26 ± 0   1.59 ± 0.57 1.74 ± 0.03 7 PMEGbisamidate 5.04 ± 7.01 >100 ± 0   >100 ± 0   >20 Example 11 PMEG phenoxyamidate 7.56 ± 0.63 >100 ± 0   >100 ± 0   >13 Example 10ODE-(3-Cl-Bn)-PMEG 0.22 ± 0.19 >0.4 ± 0    1.11 ± 0.27 5 Cidofovir 41.71± 12   >300 ± 0   >300 ± 0   >7

Example 22. Cytotoxicity Assay

Cytotoxicity Assays in HEK-293 cells. Cytotoxicity assays are performedin concurrently with every antiviral assay using the same cell line andmedia to ensure the same compound exposure. For the antiviral studiesagainst HPV11 in HEK-293 cells, transfected cells are seeded induplicate plates. Following a 2 h exposure, compound dilutions areprepared in both the antiviral plate and the duplicate cytotoxicityplate. At 48 h following compound addition, CELLTITER-GLO® (Promega) isadded to each well and luminescence is determined on a luminometer.Concentrations of compounds sufficient to reduce cell viability by 50%are calculated from the experimental data (CC₅₀ values).

Cytotoxicity Assays in Primary Human Foreskin Fibroblast Cells.Cytotoxicity was also evaluated in human foreskin fibroblast (HFF) cellsas they are a highly sensitive indicator of toxicity in a standard assaywith 7 d of compound exposure. A total of 4000 cells/well are seeded in384-well plates in cell culture media containing 2% fetal bovine serumand antibiotics. Following a 24 h incubation, 5-fold compound dilutionsare performed in duplicate wells directly in the plates containingmonolayers of HFF cells. At 7 d following compound addition,CELLTITER-GLO® reagent is added to each well and resulting luminescenceis measured on a luminometer to assess the number of viable cells ineach well. Data are then used to calculate CC₅₀ values. The data isdisclosed in Table 3 below.

TABLE 3 Cytotoxicity Results (CELLTITER-GLO ®) (CC₅₀, μM) HEK 293 HFFCompound (2 d incubation) (7 d incubation) ODE-(4-Me-Bn)-PMEG 32.01 ±8.14  6.02 ± 3.79 ODE-(3-F-4-OMe-Bn)-PMEG 13.08 ± 5.17  1.72 ± 0.66ODE-(3-Cl-4-OMe-Bn)-PMEG 8.87 ± 1.20 2.27 ± 0.51 ODE-(3-F-Bn)-PMEG 2.16± 0.36 6.88 ± 4.92 PMEG bisamidate >100 ± 0   >100 ± 0   Example 11 PMEGphenoxy amidate >100 ± 0   70.93 ± 4.07  Example 10 ODE-(3-Cl-Bn)-PMEG 1.0 ± 0.16 4.65 ± 1.73 Cidofovir >300 ± 0   >300 ± 0  

Example 23. Synthesis of9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, TributylamineSalt, 1, Alternate Name:((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonic acid,Tributylamine Salt

The scheme above provides a chemical synthetic scheme to afford9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt.

Example 24. Synthesis of octadecyloxyethyl9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine

Example 25. Synthesis of benzyl9-[(2-phosphonomethoxy)ethyl]6-O-Me-guanine

Example 26. Synthesis of 1-O-octadecyl-2-O-benzyl-sn-glyceryl9-[(2-phosphono-methoxy)ethyl]6-O-Me-guanine

Example 27. Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl Hydrogen((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate

Example 28. Synthesis ofS,S′-(((((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))diethanethioate

Example 29. Synthesis of bis(2-((2-hydroxyethyl)sulfinothioyl)ethyl)((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)phosphonate

Example 30. Synthesis of2-amino-9-(2-((4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl)methoxy)ethyl)-1,9-dihydro-6H-purin-6-one

Example 31. Synthesis of2-((2-(2-amino-6-hydroxy-9H-purin-9-yl)ethoxy)methyl)-8-(tert-butyl)-4H-benzo[d][1,3,2]dioxaphosphinine2-oxide

Example 32. Synthesis of (5-nitrofuran-2-yl)methylP-((2-(2-amino-6-methoxy-9H-purin-9-yl)ethoxy)methyl)-N-(4-chlorobutyl)-N-methylphosphonamidate

Example 33. Synthesis of Dibenzyl PMEG

Dibenzyl PMEG can be prepared from benzyl PMEG, Example 4, asillustrated below.

Example 34. Synthesis of dibenzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine

Dibenzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine can be preparedfrom 9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine,tributylamine salt (Example 23).

Example 35. Synthesis of octadecyloxyethyl benzyl9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine

The compound octadecyloxyethyl benzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine can be prepared from9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt (Example 23) as illustrated below.

Example 36. Synthesis of hexadecyloxypropyl benzyl9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine

The compound hexadecyloxypropyl benzyl 9-[(2-phosphonomethoxyl)ethyl]6-OMe-guanine can be prepared from9-[(2-phosphonomethoxy)ethyl]-2-amino-6-methoxypurine, tributylaminesalt (Example 23) as illustrated below.

Example 37. Synthesis of a Nitrofuranylmethyl PMEG Prodrug

Benzyl PMEG is treated with 5-nitrofurfuryl alcohol, ByBOP,diisopropylethylamine, and N,N-dimethylformamide for 18 hours at roomtemperature as illustrated below.

Example 38. Synthesis of a Nitrofuranylmethyl Benzyl Prodrug

The compound benzyl 9-[(2-phosphonomethoxyl)ethyl] 6-OMe-guanine istreated with 5-nitrofurfuryl alcohol, ByBOP, diisopropylethylamine, andN,N-dimethylformamide for 18 hours at room temperature as illustratedbelow.

Example 39. Synthesis of9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine

The compound9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]guanine issynthesized as illustrated below.

Example 40. Synthesis of9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine

The compound9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]guanine issynthesized as illustrated below.

Example 41. Synthesis of9-[2-(benzyloxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine

The compound 9-[2-(phenoxy-(ethoxy-D-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine is synthesized as illustrated below.

Example 42. Synthesis of9-[2-(benzyloxy-(ethoxy-L-alanyl)-phosphonomethoxyl)ethyl]6-OMe Guanine

The compound 9-[2-(phenoxy-(benzyloxy-L-alanyl)-phosphonomethoxyl)ethyl]6-OMe guanine is synthesized as illustrated below.

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe disclosure.

Embodiments

Embodiments disclosed herein include Embodiments P1 to P8 following.

Embodiment P1. A compound of the structure of Formula (I), or apharmaceutically acceptable salt thereof:

wherein: B¹ is a naturally occurring purine, a naturally occurringpyrimidine, a non-naturally occurring purine or a non-naturallyoccurring pyrimidine; Z¹ and Z² are independently O or NR^(Z); R^(Z) ishydrogen or an optionally substituted C₁₋₄ alkyl; R¹ is an optionallysubstituted —C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄ alkynyl, anoptionally substituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkyl(C₁-C₄alkyl)-, an optionally substituted cycloalkenyl, an optionallysubstituted cycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl,an optionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-,

and R² is an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or R¹ and R² can be taken together to form a moiety selected from anoptionally substituted or an optionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is hydrogen, optionallysubstituted alkyl or optionally substituted heteroalkyl; each R⁴ isindependently hydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A);each R^(4A) is independently hydrogen, an optionally substituted C₁₋₂₄alkyl or an optionally substituted aryl; each R⁵, each R⁶ and each R⁸are independently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰are independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;each a and each b are independently 1, 2, 3 or 4; and each c and each dare independently 0, 1, 2 or 3.

Embodiment P2. The compound of embodiment P1, wherein B¹ is:

wherein: R¹³ is unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆cycloalkyl.

Embodiment P3. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Embodiment P4. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Embodiment P5. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Embodiment P6. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Embodiment P7. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Embodiment P8. A compound of the formula:

wherein B¹ is adenine, hypoxanthine, xanthine, theobromine, caffeine,uric acid, isoguanine, 2,6-diaminopurine, cytosine, thymine or uracil,5-fluorouracil, 5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; andR¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl),(heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy,isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl,sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, mono-substituted amino group or adi-substituted amino group, and wherein the phenyl ring can besubstituted by R¹² 1, 2 or 3 times, or its pharmaceutically acceptablesalt.

Further embodiments include Embodiments 1 to 24 following.

Embodiment 1. A compound of the structure of Formula (I), or apharmaceutically acceptable salt thereof:

wherein: B¹ is selected from adenine, hypoxanthine, xanthine,theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine,cytosine, thymine or uracil, guanine-7-yl, adenine-9-yl, cytosine-1-yl,thymin-1-yl, uracil-1-yl, 2,6-diaminopurin-9-yl, 5-fluorouracil,5-fluorocytosine, 7-deazaguanine or 9-deazaguanine; Z¹ and Z² areindependently O or NR^(Z); R^(Z) is hydrogen or an optionallysubstituted C₁₋₄ alkyl; R¹ is an optionally substituted —C₂₋₂₄ alkenyl,an optionally substituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl), an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, an optionally substituted heterocyclyl(C₁-C₄ alkyl)-,

and R² is an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or R¹ and R² can be taken together to form a moiety selected from anoptionally substituted or an optionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is hydrogen, optionallysubstituted alkyl or optionally substituted heteroalkyl; each R⁴ isindependently hydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A);each R^(4A) is independently hydrogen, an optionally substituted C₁₋₂₄alkyl or an optionally substituted aryl; each R⁵, each R⁶ and each R⁸are independently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰are independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;each a and each b are independently 1, 2, 3 or 4; and each c and each dare independently 0, 1, 2 or 3.

Embodiment 2. A compound of the structure of Formula (I), or apharmaceutically acceptable salt thereof:

wherein: B¹ is guanine; Z¹ and Z² are independently O or NR^(Z); R^(Z)is hydrogen or an optionally substituted C₁₋₄ alkyl; R¹ is an optionallysubstituted —C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄ alkynyl, anoptionally substituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkyl(C₁-C₄alkyl)-, an optionally substituted cycloalkenyl, an optionallysubstituted cycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl,an optionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-,

and R² is an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or R¹ and R² can be taken together to form a moiety selected from anoptionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is optionally substitutedalkyl or optionally substituted heteroalkyl; each R⁴ is independentlyhydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A)is independently hydrogen, an optionally substituted C₁₋₂₄ alkyl or anoptionally substituted aryl; each R⁵, each R⁶ and each R⁸ areindependently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₅ alkenyl, an optionally substituted C₂₋₅ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰are independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;each a and each b are independently 1, 2, 3 or 4; and each c and each dare independently 0, 1, 2 or 3.

Embodiment 3. A compound of the structure of Formula (I), or apharmaceutically acceptable salt thereof:

wherein: B¹ is

Z¹ and Z² are independently O or NR^(Z); R^(Z) is hydrogen or anoptionally substituted C₁₋₄ alkyl; R¹ is an optionally substituted—C₂₋₂₄ alkenyl, an optionally substituted —C₂₋₂₄ alkynyl, an optionallysubstituted —(CHR⁴)_(a)—O—C₂₋₂₄ alkenyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkyl(C₁-C₄ alkyl)-, anoptionally substituted cycloalkenyl, an optionally substitutedcycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl), an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-,

and R² is an optionally substituted —C₂₋₂₄ alkenyl, an optionallysubstituted —C₂₋₂₄ alkynyl, an optionally substituted—(CHR⁴)_(b)—O—C₂₋₂₄ alkenyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁₋₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁₋₄alkyl)-, substituted aryl(C₁₋₄ alkyl)-,

or R¹ and R² can be taken together to form a moiety selected from anoptionally substituted

or an optionally substituted

wherein Z¹, Z², R¹ and R², the phosphorus and the moiety form asix-membered to ten-membered ring system; R³ is optionally substitutedalkyl or optionally substituted heteroalkyl; each R⁴ is independentlyhydrogen, —(CH₂)_(c)—S—C₁₋₂₄ alkyl or —O—(CH₂)_(d)—R^(4A); each R^(4A)is independently hydrogen, an optionally substituted C₁₋₂₄ alkyl or anoptionally substituted aryl; each R⁵, each R⁶ and each R⁸ areindependently an optionally substituted C₁₋₈ alkyl, an optionallysubstituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈ alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁷ isindependently hydrogen, an optionally substituted C₁₋₈ alkyl, anoptionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; each R⁹ and each R¹⁰are independently hydrogen or an optionally substituted C₁₋₆ alkyl;—CH₂SH, —CH₂(C═O)NH₂, —CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionallysubstituted phenyl, —CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; each R¹¹ is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkyl(C₁-C₄ alkyl)-, an optionallysubstituted cycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄alkyl)-, an optionally substituted aryl, an optionally substitutedaryl(C₁₋₄ alkyl)-, an optionally substituted heteroaryl, an optionallysubstituted heteroaryl(C₁-C₄ alkyl)-, an optionally substitutedheterocyclyl, or an optionally substituted heterocyclyl(C₁-C₄ alkyl)-;R¹³ is unsubstituted C₁₋₆ alkyl or an unsubstituted C₃₋₆ cycloalkyl;each a and each b are independently 1, 2, 3 or 4; and each c and each dare independently 0, 1, 2 or 3.

Embodiment 4. The compound of embodiment 1, wherein B¹ is:

Embodiment 5. A compound of the formula:

wherein: R¹² is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl),cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; p=1, 2, 3, 4 or 5; and B¹ and R³ are asdefined in embodiment 1; or its pharmaceutically acceptable salt.

Embodiment 6. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 7. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R⁵ is an optionally substituted C₁₋₈ alkyl,an optionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl,cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, amono-substituted amino group or a di-substituted amino group; and B¹ andR³ are as defined in embodiment 1; or its pharmaceutically acceptablesalt.

Embodiment 8. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R⁶ is an optionally substituted C₁₋₈ alkyl,an optionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl,cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, amono-substituted amino group or a di-substituted amino group; and B¹ andR³ are as defined in embodiment 1; or its pharmaceutically acceptablesalt.

Embodiment 9. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R is independently hydrogen, an optionallysubstituted C₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, anoptionally substituted C₂₋₈ alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkyl(C₁-C₄ alkyl)-, anoptionally substituted cycloalkenyl, an optionally substitutedcycloalkenyl(C₁-C₄ alkyl)-, an optionally substituted aryl, anoptionally substituted aryl(C₁₋₄ alkyl)-, an optionally substitutedheteroaryl, an optionally substituted heteroaryl(C₁-C₄ alkyl)-, anoptionally substituted heterocyclyl, or an optionally substitutedheterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 10. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R⁸ is an optionally substituted C₁₋₈ alkyl,an optionally substituted C₂₋₈ alkenyl, an optionally substituted C₂₋₈alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl,cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, amono-substituted amino group or a di-substituted amino group; and B¹ andR³ are as defined in embodiment 1; or its pharmaceutically acceptablesalt.

Embodiment 11. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 12. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 13. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; each R⁹ and each R¹⁰ are independentlyhydrogen or an optionally substituted C₁₋₆ alkyl; —CH₂SH, —CH₂(C═O)NH₂,—CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-an optionally substituted phenyl,—CH₂OH, —CH(OH)CH₃,

—CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

and —(CH₂)₄NH₂; R¹¹ is independently hydrogen, an optionally substitutedC₁₋₈ alkyl, an optionally substituted C₂₋₈ alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkyl(C₁-C₄ alkyl)-, an optionally substitutedcycloalkenyl, an optionally substituted cycloalkenyl(C₁-C₄ alkyl)-, anoptionally substituted aryl, an optionally substituted aryl(C₁₋₄alkyl)-, an optionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(alkyl), cycloalkenyl,cycloalkenyl(alkyl), aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano,halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, amino, amono-substituted amino group or a di-substituted amino group; and B¹ andR³ are as defined in embodiment 1; or its pharmaceutically acceptablesalt.

Embodiment 14. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R⁸ is an optionally substituted C₁₋₈ alkyl,an optionally substituted C₂₋₅ alkenyl, an optionally substituted C₂₋₅alkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkyl(C₁-C₄ alkyl)-, an optionally substituted cycloalkenyl, anoptionally substituted cycloalkenyl(C₁-C₄ alkyl)-, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₄ alkyl)-, anoptionally substituted heteroaryl, an optionally substitutedheteroaryl(C₁-C₄ alkyl)-, an optionally substituted heterocyclyl, or anoptionally substituted heterocyclyl(C₁-C₄ alkyl)-; and B¹ and R³ are asdefined in embodiment 1; or its pharmaceutically acceptable salt.

Embodiment 15. A compound of the formula:

wherein: B and R are as defined in embodiment 1; or its pharmaceuticallyacceptable salt.

Embodiment 16. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 17. A compound of the formula:

wherein: p=1, 2, 3, 4 or 5; R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; and B¹ and R³ are as defined in embodiment1; or its pharmaceutically acceptable salt.

Embodiment 18. A pharmaceutical composition comprising an effectiveamount of a compound of any one of embodiments 1-17, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

Embodiment 19. The pharmaceutical composition of embodiment 18, whereinthe pharmaceutical composition is in the form of a cream, a gel or anointment.

Embodiment 20. The pharmaceutical composition of embodiment 18 or 19,wherein the pharmaceutical composition is a topical formulation.

Embodiment 21. Use of a compound of any one of embodiments 1-17, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for treating a viral disease in a subject in need thereof,wherein the viral disease is human papilloma virus.

Embodiment 22. The use of embodiment 21, said compound, or apharmaceutically acceptable salt thereof, for use in treating aplurality of types of human papilloma virus.

Embodiment 23. The use of embodiment 21, wherein the human papillomavirus is selected from the group consisting human papilloma virusHPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52,HPV-56, HPV-58, HPV-59, HPV-68, HPV-73 and HPV-82.

Embodiment 24. Use of a compound of any one of embodiments 1-17, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for treating cancer of the cervix in a subject in needthereof.

We claim:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: B¹ is

R³ is alkyl or heteroalkyl; each R⁹ and each R¹⁰ are independentlyselected from hydrogen, C₁₋₆ alkyl, —CH₂SH, —CH₂(C═O)NH₂,—CH₂CH₂(C═O)NH₂, —CH₂CH₂S CH₃, CH₂-phenyl, —CH₂OH, —CH(OH)CH₃,

 —CH₂(C═O)OH, —CH₂CH₂(C═O)OH, —(CH₂)₃NH(C═NH)NH₂,

 and —(CH₂)₄NH₂; R¹¹ is independently selected from hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, alkynyl, cycloalkyl, cycloalkyl(C₁-C₄ alkyl)-,cycloalkenyl, cycloalkenyl(C₁-C₄ alkyl)-, aryl, aryl(C₁₋₄ alkyl)-,heteroaryl, heteroaryl(C₁-C₄ alkyl)-, heterocyclyl, andheterocyclyl(C₁-C₄ alkyl)-; R¹² is alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl(alkyl), cycloalkenyl, cycloalkenyl(alkyl), aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl,hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl,N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,tnhalomethanesulfonamido, amino, a mono-substituted amino group or adi-substituted amino group; R¹³ is unsubstituted C₁₋₆alkyl orunsubstituted C₃₋₆cycloalkyl; and p is selected from 1, 2, 3, 4, and 5.2. The compound of claim 1, wherein B¹ is


3. The compound of claim 2, wherein R¹³ is methyl.
 4. The compound ofclaim 1, wherein B¹ is


5. The compound of claim 1, wherein R³ is CH₃, CH₂OH, or CH₂F.
 6. Thecompound of claim 1, wherein R⁹ is C₁₋₆alkyl.
 7. The compound of claim1, wherein R¹⁰ is hydrogen.
 8. The compound of claim 1, wherein R¹¹ isC₁₋₈alkyl.
 9. The compound of claim 1, wherein R¹² is alkyl.
 10. Thecompound of claim 1, wherein R¹² is hydroxy.
 11. The compound of claim1, wherein R¹² is halogen.
 12. The compound of claim 1, wherein p is 1.13. A pharmaceutical composition comprising an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable excipient.
 14. The pharmaceuticalcomposition of claim 13, wherein the pharmaceutical composition is atopical formulation.
 15. The pharmaceutical composition of claim 14,wherein the pharmaceutical composition is in the form of a cream, gel,or an ointment.
 16. A method for treating human papilloma viruscomprising administering a compound of claim 1 or a pharmaceuticallyacceptable salt thereof in a human in need thereof.
 17. A method fortreating cervical intraepithelial neoplasia, vaginal intraepithelialneoplasia, or anal intraepithelial neoplasia comprising administering acompound of claim 1 or a pharmaceutically acceptable salt thereof in ahuman in need thereof.